Insulin Signalling

Question 1

When is diabetes diagnosed?

Answer 1

When blood glucose levels are not controlled properly

Hypergylcemia

Question 2

Insulin?

Answer 2

Major hormone

Prevents hyperglycemia and therefore diabetes

Question 3

Hyperglycemia?

Answer 3

High blood glucose levels in the body

Question 4

Major function of insulin?

Answer 4

To prepare the body for incoming nutrients

Promoting storage, thereby preventing nutrient toxicity

Question 5

What 3 processes does insulin do within the cell?

Answer 5

Insulin stimulates glucose uptake into the cell.

Turns off glucose production after a meal.

Stimualtes glucose storage as glycogen

Question 6

7 Major diseases caused by insulin signalling?

Answer 6

Type 2 diabetes: defective insulin signalling.

Heart disease: abnormal vascular signalling

Obesity: abnormal appetitie and thermogenesis

Immune disease: defective immunoreactivity.

Neurodegeneration: abnormal apoptosis

Cancer: abnormal growth signal

Epilepsy: abnormal neuronal signalling

Question 7

The process of signalling?

Answer 7

External signal: such as hormone or neurotransmitter- transfers info between cells.

Receptor: functions to detect the external signals.

Transducer: Receives info from receptors and transform it into different types of info.

Effectors: Specific cellular process.

Question 8

Why is intracellular communication needed?

Answer 8

Respond to environemnt

Adjust to state of cell/tissue (DNA damage, cell cycle etc)

Question 9

What is an insulin receptor?

Answer 9

Tyrosine kinase associated receptor

Membrane bound.

alpha and beta domains.

Question 10

Receptor tyrosine kinase classes are defined by?

How many classes are there?

Answer 10

Defined by their ligands

Lots and lots of classes

eg. EGF, FGF, Insulin

Question 11

Reaction to get from ionositol into phosphoinositide and then into PI kinase?

Answer 11

Inositol —–(ATP->ADP)—> Phosphoinositols

Phosphoionositides——-(ATP->ADP)—–>PI Kinase

Specifically phosphorylates 3-position of ring.

Question 12

PI3-kinase used as?

Answer 12

Used to phosphorylate different phosphatidyl inositols.

PIP₂-> PIP₃

This is the major reaction involved in insulin and GF signalling

Question 13

What two enzymes are in balance for the ratio PIP₂:PIP₃?

Answer 13

PI3-kinase

PTEN (lipid phosphatase)

Additionally SHIP (5-Ppase)

Question 14

Name some of the physiological agents that induce PIP3 levels?

Answer 14

EGF

FGF

GH

Insulin

Leptin

IGF-1

Question 15

What does PIP3 bind to?

Answer 15

Binds to the PH domain

Alters their function

Question 16

Protein phosphorylation?

Answer 16

Key to transucing insulin action.

Reversible method.

Question 17

What group can proteins get phosphorylated on?

Answer 17

Any hydroxyl group

Introduces a large negative charge into the protein structure

Question 18

Serine/Threonine Protein Kinases?

Answer 18

Primarily cytosolic and nuclear.

Question 19

Tyrosine Protein Kinases?

Answer 19

Primarily receptor linked

Question 20

Dual specifcity protein kinases?

Answer 20

Small number of protein kinases

Can phosphorylate Ser/Thr or tyrosine.

Question 21

Effects of protein phosphorylation?

Answer 21

Enzyme activation/inhibition

Interaction with other proteins.

Cellular localisation

Stability

Question 22

What other conditions do specific protein kinase inhibitors treat?

Answer 22

Cancer

Early trials: immunological, metabolic and neurological diseases.

For the treatment for insulin resistance

Question 23

the two specific pathways involved in insulin action?

Answer 23

1) PI3- kinase pathway
2) MAP kinase pathway

Question 24

What is the P13-kinase pathway?

Answer 24

Insulin binds to receptor

Causing a phosphorylation effect on the receptor.

This allows IRS to bind and become activated (by phosphorylation)

This binds to PI3-K which activates it.

Stimualtes the PIP2 to PIP3 reaction

Question 25

What is the outcome of producing PIP₃

Answer 25

Produces downstream effects Such as PDK1 GTPases GDP/GTP exchange. Adaptor proteins Tyrosine kinase

Question 26

PDK1 regulates?

Answer 26

Insulin activation of protein kinase B (AKT)

Question 27

Protein Kinase B (AKT)

Answer 27

Major enzyme in PIP₃ signalling. Key component of insulin and GF.

Question 28

MAP kinase Signalling?

Answer 28

Insulin binds to receptor. Phosphorylation of the receptor. Causes the IRS to bind. Activates GRB2:mSOS. This stimulates the activation of Ras (using ATP) Activation of Raf Activation of MAPKK (by phosphorylation) Stimulates the activation of p44MAP kinase

Question 29

MAP kinase does?

Answer 29

Stimulation of downstream affectors. Gene transcription growth (including CREB, MSK) Neuronal strcuture: MAP2

Question 30

AKT effects?

Answer 30

**Inhibits**: GSK3 (an inhibitor of the glycogen synthesis) Glyconeogenic gene expression **Stimulates**: GLUT4 translocation. Protein translation

Question 31

Protein tyrosine phosphatase 1B?

Answer 31

Turns off the insulin signalling By interferring with the MAP kinase and PI3 kinase pathway

Question 32

Negative feedback within MAP kinase pathway?

Answer 32

Downstream production of MAPK phosphatas Inhibits the MAPK.

Question 33

Type 2 diabetes are found to have what wrong with these pathways?

Answer 33

Defective insulin signalling. Could be due to insulin antagonist (PTP1B, IRS1 kinase)

Question 34

What causes PIP3 to break down to PIP2?

Answer 34

PTEN Lipid phosphatase

Question 35

Insulin resistance

Answer 35

Reduced sensitivity to insulin Molecular, cellular , tissue or whole organism

Question 36

Therapy to fix and re-sensitive to insulin

Answer 36

Need a good diagnosis on what has went wrong as there is numerous reasons why someone has become insulin resistant.

Question 37

Naem the 3 Regulators of insulin signalling ? Why are they important?

Answer 37

1. PTP1B inhibitors 2. GSK-3 inhibitors 3. AMPK activators Important for current research to overcome insulin resistance

Question 38

What does PTP1B do?

Answer 38

Turns off insulin signalling. Therefore no longer MAP kinase or PI3 kinase pathway

Question 39

Inhibitors of PTP1B activity?

Answer 39

Increase the insulin receptor activity. Being developed for the treatment of diabetes.

Question 40

GSK3 inhibitors?

Answer 40

Being developed for the treatment of diabetes. Restore the effect of insulin on GSK3 activity.

Question 41

Insulin and diabetes?

Answer 41

In diabetes there is a reduced insulin sensitivity Leads to enhanced insulin production to compensate. Asymptomatic: no symptoms.

Question 42

When can type 2 diabetes be diagnosed?

Answer 42

When the pancreas can no longer make enough insulin to overcome the insulin resistance.

Question 43

Difference between type 1 and type 2 diabetes?

Answer 43

The pre-diabetes stage. T2 patients have relatively high levels of insulin but the cells are resistant to it while T1 patients make little insulin.

Question 44

What are the risk factors for T2 diabetes?

Answer 44

Environmental Diet Exercise Obesity.