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E: Regulatory Physiology & Pharmacology > Insulin Signalling > Flashcards

Insulin Signalling Flashcards

1
Q

When is diabetes diagnosed?

A

When blood glucose levels are not controlled properly

Hypergylcemia

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2
Q

Insulin?

A

Major hormone

Prevents hyperglycemia and therefore diabetes

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3
Q

Hyperglycemia?

A

High blood glucose levels in the body

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4
Q

Major function of insulin?

A

To prepare the body for incoming nutrients

Promoting storage, thereby preventing nutrient toxicity

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5
Q

What 3 processes does insulin do within the cell?

A

Insulin stimulates glucose uptake into the cell.

Turns off glucose production after a meal.

Stimualtes glucose storage as glycogen

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6
Q

7 Major diseases caused by insulin signalling?

A

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

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7
Q

The process of signalling?

A

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.

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8
Q

Why is intracellular communication needed?

A

Respond to environemnt

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

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9
Q

What is an insulin receptor?

A

Tyrosine kinase associated receptor

Membrane bound.

alpha and beta domains.

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10
Q

Receptor tyrosine kinase classes are defined by?

How many classes are there?

A

Defined by their ligands

Lots and lots of classes

eg. EGF, FGF, Insulin

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11
Q

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

A

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

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

Specifically phosphorylates 3-position of ring.

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12
Q

PI3-kinase used as?

A

Used to phosphorylate different phosphatidyl inositols.

PIP2-> PIP3

This is the major reaction involved in insulin and GF signalling

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13
Q

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

A

PI3-kinase

PTEN (lipid phosphatase)

Additionally SHIP (5-Ppase)

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14
Q

Name some of the physiological agents that induce PIP3 levels?

A

EGF

FGF

GH

Insulin

Leptin

IGF-1

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15
Q

What does PIP3 bind to?

A

Binds to the PH domain

Alters their function

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16
Q

Protein phosphorylation?

A

Key to transucing insulin action.

Reversible method.

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17
Q

What group can proteins get phosphorylated on?

A

Any hydroxyl group

Introduces a large negative charge into the protein structure

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18
Q

Serine/Threonine Protein Kinases?

A

Primarily cytosolic and nuclear.

19
Q

Tyrosine Protein Kinases?

A

Primarily receptor linked

20
Q

Dual specifcity protein kinases?

A

Small number of protein kinases

Can phosphorylate Ser/Thr or tyrosine.

21
Q

Effects of protein phosphorylation?

A

Enzyme activation/inhibition

Interaction with other proteins.

Cellular localisation

Stability

22
Q

What other conditions do specific protein kinase inhibitors treat?

A

Cancer

Early trials: immunological, metabolic and neurological diseases.

For the treatment for insulin resistance

23
Q

the two specific pathways involved in insulin action?

A

1) PI3- kinase pathway
2) MAP kinase pathway

24
Q

What is the P13-kinase pathway?

A

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

25
Q

What is the outcome of producing PIP3

A

Produces downstream effects

Such as PDK1

GTPases

GDP/GTP exchange.

Adaptor proteins

Tyrosine kinase

26
Q

PDK1 regulates?

A

Insulin activation of protein kinase B (AKT)

27
Q

Protein Kinase B (AKT)

A

Major enzyme in PIP3signalling.

Key component of insulin and GF.

28
Q

MAP kinase Signalling?

A

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

29
Q

MAP kinase does?

A

Stimulation of downstream affectors.

Gene transcription growth (including CREB, MSK)

Neuronal strcuture: MAP2

30
Q

AKT effects?

A

Inhibits:

GSK3 (an inhibitor of the glycogen synthesis)

Glyconeogenic gene expression

Stimulates:

GLUT4 translocation.

Protein translation

31
Q

Protein tyrosine phosphatase 1B?

A

Turns off the insulin signalling

By interferring with the MAP kinase and PI3 kinase pathway

32
Q

Negative feedback within MAP kinase pathway?

A

Downstream production of MAPK phosphatas

Inhibits the MAPK.

33
Q

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

A

Defective insulin signalling.

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

34
Q

What causes PIP3 to break down to PIP2?

A

PTEN

Lipid phosphatase

35
Q

Insulin resistance

A

Reduced sensitivity to insulin

Molecular, cellular , tissue or whole organism

36
Q

Therapy to fix and re-sensitive to insulin

A

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

37
Q

Naem the 3 Regulators of insulin signalling ?

Why are they important?

A
  1. PTP1B inhibitors
  2. GSK-3 inhibitors
  3. AMPK activators

Important for current research to overcome insulin resistance

38
Q

What does PTP1B do?

A

Turns off insulin signalling.

Therefore no longer MAP kinase or PI3 kinase pathway

39
Q

Inhibitors of PTP1B activity?

A

Increase the insulin receptor activity.

Being developed for the treatment of diabetes.

40
Q

GSK3 inhibitors?

A

Being developed for the treatment of diabetes.

Restore the effect of insulin on GSK3 activity.

41
Q

Insulin and diabetes?

A

In diabetes there is a reduced insulin sensitivity

Leads to enhanced insulin production to compensate.

Asymptomatic: no symptoms.

42
Q

When can type 2 diabetes be diagnosed?

A

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

43
Q

Difference between type 1 and type 2 diabetes?

A

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.

44
Q

What are the risk factors for T2 diabetes?

A

Environmental

Diet

Exercise

Obesity.

E: Regulatory Physiology & Pharmacology (15 decks)

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