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Diabetes > Abnormal insulin signalling > Flashcards

Abnormal insulin signalling Flashcards

1
Q

Describe the insulin receptor

A

Receptor tyrosine kinase
A membrane receptor
When activated by a ligand (insulin) dimerises and autophosphorylates
Has 2 alpha subunits and 2 beta subunits

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2
Q

What are the subunits of the insulin receptor?

A 
2 alpha subunits and 2 beta subunits
Alpha subunits are extracellular
Beta subunits are intracellular
Alpha represses beta activity until insulin binds
Beta subunits phosphorylate
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3
Q

What is the IGF1R?

A

IGF-1 receptor
Homology with the IR
Causes some cross-reactivity

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4
Q

What is critical node 1?

A

The insulin receptor and associated insulin responsive substrate node

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5
Q

What is the role of the IR and IRS?

A

Mediate binding of intracellular effectors

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6
Q

What are similarities between the IR and IRS?

A

Activated by tyrosine phosphorylation

Negatively regulated by tyrosine phosphatases, serine phosphorylation and ligand induced downregulation

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7
Q

What does IRS stand for?

A

Insulin responsive substrate node

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8
Q

What else can the IR be downregulated by?

A

Sterically blocking

eg 1PC1 or 10Grb10

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9
Q

What are the effects of IRS?

A

There are 6 IRS proteins (1-6)

1: glucose uptake
2: MAPK activation

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10
Q

What is the effect of decreased IRS protein levels?

A

Insulin resistance

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11
Q

What is the effect of decreased hepatic IRS 1 and 2?

A

1: Increased expression of genes that regulate gluconeogenesis
2: Increased expression of genes involved in lipogenesis

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12
Q

What is critical node 2?

A

PI3K

Regulatory and catalytic subunits with several isoforms

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13
Q

What is the role of critical node 2?

A

Mediates almost all of insulins metabolic actions
Activates regulators of insulin signalling
Catalyses the formation of lipid second messenger, phophoinositol triphosphate PIP3

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14
Q

What is pleckstrin homology?

A

Proteins with pleckstrin homology domains can bind to PIP3
Localise and activate
eg. 3-phospho-inositide-dependent protein kinase 1
Allows for compartmentalisation in the cell

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15
Q

What recruits PI3K?

A

Phosphorylated IRS1

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16
Q

What is critical node 3?

A

Protein kinase B (Akt)

17
Q

What does critical node 3 do?

A

Mediates most of PI3K-mediated metabolic actions

Via phosphorylation of other proteins, signalling molecules and transcription factors

18
Q

What is glycogen synthase kinase 3?

A

Phosphorylated by protein kinase B
Decreases suppression of glycogen synthase
Glycogenesis

19
Q

How does the critical node 3 regulate glucose uptake?

A

Phosphorylates and inhibits Rab-GTP-ase activating protein AS160
Triggers translocation of Glut4 to cell membrane

20
Q

How does critical node 3 regulate mTOR?

A

Phosphorylates and inhibits TSC1 and 2
These are mTOR inhibitors
mTOR activated

21
Q

How does critical node 3 regulate gluconeogenic and lipogenic enzymes?

A

Controls activity of FOX transcription factors

22
Q

Describe Glut4

A

In basal state: perinuclear depot, cytosol-dispersed vesicles
In response to insulin: 20% in muscle and 50% in fat rapidly reaches the cell membrane
Rab-GTP-ase activation needed
Insulin signalling organises actin filaments to move Glut4

23
Q

What is leprechaunism?

A 
Also known as Donohue syndrome
Newborn babies
Underweight
Androgen excess
Growth retarded
Swings of blood glucose
Very high insulin levels >300pM/L
24
Q

What is a normal insulin level?

A

130pM/L

25
Q

What is the cause of leprechaunism?

A

Mutation in either the alpha or beta subunit of the IR

26
Q

How is leprechaunism treated?

A

With recombinant human IGF-1

27
Q

What are markers of inflammatory stress and metabolic stress?

A

TNFalpha

FFA, ROS, hyperglycaemia, hyperinsulinaemia

28
Q

What are consequences of inflammatory stress and metabolic stress?

A

Mitochondrial dysfunction
ER stress
Serine kinases

29
Q

What do serine kinases do?

A

Serine phosphorylation inactivates IRS1
Less glucose uptake
Increase hyperglycaemia

30
Q

What does TNFalpha block?

A

IRS action

via JNK

31
Q

What are the symptoms of Alstrom syndrome?

A 
Excessive weight gain in infancy
Blindness, deafness
10 years: fatty liver
14 years: type 2 diabetes
Grossly insulin resistant
32
Q

What is the cause of Alstrom disease?

A 
A ciliopathy disease
ALMS1 has a role in endosome recycling
ALMS1 localises to basal body of primary cilium
Has a role in transporting cargo
Glut4 trafficked by Alstrom
33
Q

How is Alstrom disease treated?

A

Currently no treatment

34
Q

What is the effect of PI3K mutations

A 
Activating mutations
Mosaic overgrowth with fibroadipose hyperplasia
Segmental overgrowth symptoms
Non-malignant
Malignant
35
Q

How are PI3K activating mutations treated?

A

mTOR inhibitor Rapamycin

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