Abnormal insulin signalling

Question 1

Describe the insulin receptor

Answer 1

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

Question 2

What are the subunits of the insulin receptor?

Answer 2

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

Question 3

What is the IGF1R?

Answer 3

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

Question 4

What is critical node 1?

Answer 4

The insulin receptor and associated insulin responsive substrate node

Question 5

What is the role of the IR and IRS?

Answer 5

Mediate binding of intracellular effectors

Question 6

What are similarities between the IR and IRS?

Answer 6

Activated by tyrosine phosphorylation

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

Question 7

What does IRS stand for?

Answer 7

Insulin responsive substrate node

Question 8

What else can the IR be downregulated by?

Answer 8

Sterically blocking

eg 1PC1 or 10Grb10

Question 9

What are the effects of IRS?

Answer 9

There are 6 IRS proteins (1-6)

1: glucose uptake
2: MAPK activation

Question 10

What is the effect of decreased IRS protein levels?

Answer 10

Insulin resistance

Question 11

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

Answer 11

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

Question 12

What is critical node 2?

Answer 12

PI3K

Regulatory and catalytic subunits with several isoforms

Question 13

What is the role of critical node 2?

Answer 13

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

Question 14

What is pleckstrin homology?

Answer 14

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

Question 15

What recruits PI3K?

Answer 15

Phosphorylated IRS1

Question 16

What is critical node 3?

Answer 16

Protein kinase B (Akt)

Question 17

What does critical node 3 do?

Answer 17

Mediates most of PI3K-mediated metabolic actions

Via phosphorylation of other proteins, signalling molecules and transcription factors

Question 18

What is glycogen synthase kinase 3?

Answer 18

Phosphorylated by protein kinase B
Decreases suppression of glycogen synthase
Glycogenesis

Question 19

How does the critical node 3 regulate glucose uptake?

Answer 19

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

Question 20

How does critical node 3 regulate mTOR?

Answer 20

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

Question 21

How does critical node 3 regulate gluconeogenic and lipogenic enzymes?

Answer 21

Controls activity of FOX transcription factors

Question 22

Describe Glut4

Answer 22

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

Question 23

What is leprechaunism?

Answer 23

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

Question 24

What is a normal insulin level?

Answer 24

130pM/L

Question 25

What is the cause of leprechaunism?

Answer 25

Mutation in either the alpha or beta subunit of the IR

Question 26

How is leprechaunism treated?

Answer 26

With recombinant human IGF-1

Question 27

What are markers of inflammatory stress and metabolic stress?

Answer 27

TNFalpha | FFA, ROS, hyperglycaemia, hyperinsulinaemia

Question 28

What are consequences of inflammatory stress and metabolic stress?

Answer 28

Mitochondrial dysfunction ER stress Serine kinases

Question 29

What do serine kinases do?

Answer 29

Serine phosphorylation inactivates IRS1 Less glucose uptake Increase hyperglycaemia

Question 30

What does TNFalpha block?

Answer 30

IRS action | via JNK

Question 31

What are the symptoms of Alstrom syndrome?

Answer 31

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

Question 32

What is the cause of Alstrom disease?

Answer 32

``` 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 ```

Question 33

How is Alstrom disease treated?

Answer 33

Currently no treatment

Question 34

What is the effect of PI3K mutations

Answer 34

``` Activating mutations Mosaic overgrowth with fibroadipose hyperplasia Segmental overgrowth symptoms Non-malignant Malignant ```

Question 35

How are PI3K activating mutations treated?

Answer 35

mTOR inhibitor Rapamycin