Role of Insulin and Leptin in Vascular Disease

Question 1

List some of the key effects of insulin signalling

Answer 1

Anti-lipolysis (not breaking down fat), glucose internalization, glycogen synthesis, protein synthesis, anti-apoptosis and increased endothelial NO and endothelin-1 (ET-1) production

Question 2

List the basic ‘insulin metabolic arm’

Answer 2

Insulin -> insulin receptor -> IRS-1 -> PI3K -> Akt -> eNOS

Question 3

What pathway does insulin take to activate ET-1

Answer 3

MAPK pathway

Question 4

What does eNOS stand for

Answer 4

Endothelial nitrous oxide synthase

Question 5

What effect does NO have on the endothelium

Answer 5

Reduces expression of adhesion molecules in endothelium, promotes vasorelaxation and inhibits proliferation of vascular smooth muscle cells and platelets

Question 6

What effect does ET-1 have on the endothelium

Answer 6

Increases expression of adhesion molecules, favours platelet aggregation and promotes VSMC contraction

Question 7

Where are insulin receptors in blood vessels

Answer 7

On the endothelial and smooth muscle cells

Question 8

List the 3 key ways insulin plays a key role in regulating whole body glucose disposal in the endothelium

Answer 8

1) Transendothelial support (insulin mediated glucose disposal)
2) Vasodilation of blood vessels (eNOS and NO production)
3) Production of hormone mediators (NO and cGMP)

Question 9

List the three ways insulin acts as an anti-atherogenic in endothelial cells

Answer 9

1) Decreased endothelial cell apoptosis
2) Decreased ROS and increased antioxidant production
3) Reduced adhesion molecule expression

Question 10

What insulin pathway promotes ANGII production

Answer 10

MAPK signalling

Question 11

What ion can insulin change intracellularly to induce vascular relaxation

Answer 11

Calcium

Question 12

What insulin pathway exerts an anti-apoptotic effect

Answer 12

PI3K

Question 13

When does insulin stimulate ET-1 receptor expression

Answer 13

In moments of hyperinsulinaemia

Question 14

What are zucker and goto-kakizaki rats

Answer 14

Zucker= Obese
Goto-Kakizaki= Spontaneously hypertensive rats

Question 15

How do zucker and goto-kakizaki rats show evidence for insulin resistant vascular disease

Answer 15

Both show co-existing insulin resistance and hypertension

Question 16

What does genetically reduced insulin signalling in animal models show in atherosclerosis

Answer 16

Accelerated atherosclerosis progression

Question 17

Relationship between insulin sensitivity and vasoresponsiveness

Answer 17

Increased insulin sensitivity results in an improved vasoresponsiveness

Question 18

What three things lead to a decrease of eNOS (resulting in reduced vasodilation and subsequent endothelial dysfunction)

Answer 18

IL-6, TNF-Alpha and insulin resistance

Question 19

What are cytokines

Answer 19

Molecules produced by tissues and act to locally activate immune cells. They are abundant in obesity and T2DM. Examples include TNF-alpha, ILs and interferon gamma

Question 20

What are chemokines

Answer 20

Otherwise known as chemoattractant cytokines. They direct the movement of circulating immune cells to sites of inflammation or injury. They are released from target cells/tissues such as endothelial and VSM cells.

Question 21

What are adhesion molecules

Answer 21

Molecules that bind to specific immune cells and promote extravasation?? Dysfunctional endothelial and VSMC overexpress adhesion moeclules in response to pro-inflammatory cytokines

Question 22

What are TLRs

Answer 22

Toll like receptors are pro-inflammatory receptors which initiate inflammation.

Question 23

What TLRs are involved in atherosclerosis

Answer 23

2 and 4 (expressed on endothelial cells and macrophages

Question 24

What do lipids do to TLR2/4

Answer 24

Bind and activate them while initiating endothelial cell dysfunction and foam cell formation

Question 25

What ILs do TLRs promote and how do they do this

Answer 25

Signal through MyD88 to promote IL-1 and 12

Question 26

What does NEFA and FFA stand for

Answer 26

Non-estrified fatty acids and free fatty acids

Question 27

What parts of the body release free fatty acids

Answer 27

Hypertrophic adipocytes

Question 28

What can occur when you increase FFA in healthy subjects to the range of what it is in obesity and T2DM

Answer 28

Reduced insulin resistance, rapidly (48 hours) induces markers of endothelial activation (adhesion molecules), vascular inflammation (MPO) and thrombosis

Question 29

What receptors do saturated fatty acids bind to

Answer 29

TLR2/4

Question 30

What kinases are activated by TLR2/4

Answer 30

Ser/Thr kinases

Question 31

What do Ser/Thr kinases phosphorylate

Answer 31

IRS-1 and 2 at serine residues

Question 32

What do lipoproteins transport

Answer 32

Lipoproteins transport cholesterol from the liver to adipocytes for storage

Question 33

What lipoproteins are protective against atherosclerosis and which is a risk factor for it

Answer 33

HDL is protective against atherosclerosis and LDL initiate vascular inflammation and damage

Question 34

Why does LDL make atherosclerosis more likely when compared to HDL

Answer 34

LDL is more susceptible to oxidisation which in turn promotes foam cells formation

Question 35

Discuss briefly oxLDL and foam cells

Answer 35

1) oxLDL promotes monocyte recruitment 2) oxLDL inhibits macrophages to leave the intima into the lumen 3) oxLDL are taken up by scavenger receptors on macrophages to form foam cells 4) Foam cell promote endothelial cell injury further foam cell and immune cell recruitment 5) Foam cell necrosis

Question 36

What are the two main parts of an atherosclerotic plaque

Answer 36

The lipid centre and fibrous cap

Question 37

List all the immune cells involved in atherosclerotic plaques

Answer 37

Monocytes (macrophages), T and B cells, neutrophils and dendritic cells

Question 38

List the key molecules of reactive oxygen species

Answer 38

Superoxide, hydroxyl radicals and peroxynitrite

Question 39

What are ROS used for under physiological conditions

Answer 39

Act as signalling molecule for growth factor signalling, aerobic respiration/metabolism

Question 40

What produces ROS

Answer 40

Ang II, cytokines and LDL

Question 41

How is peroxynitrite formed and what effect does this have

Answer 41

Superoxide reacts with NO, reducing bioavailability of NO and NO uncoupling

Question 42

Name the two negative regulators of leptin signalling

Answer 42

SOCS3 and PTP1B

Question 43

How does exogenous leptin infusion increase arterial blood pressure

Answer 43

Increased endothelin-1 expression

Question 44

Is STAT3 signalling protective or a risk factor for atherosclerosis

Answer 44

Protecting

Question 45

Describe leptins actions in endothelial cells

Answer 45

Reduces apoptosis, promotes endothelial cell proliferation and induces NO production

Question 46

Describe leptins actions in VSMCs

Answer 46

Stimulates migration, hypertrophy and proliferation, NO production, calcification, leptin resistance impairs vascular responsiveness, inhibits Ang-II induced calcium increasei

Question 47

How does activation of the sympathetic nervous system indirectly contribute to atherosclerosis

Answer 47

1) Increased vasoconstriction 2) Stimulating platelet aggregation 3) Promoting insulin resistance 4) Stimulating monocyte and neutrophil production and activation

Question 48

How to measure sympathetic tone

Answer 48

Plasma noradrenaline levels

Question 49

Name the sympathetic neurotransmitters that promote proliferation and hypertrophy

Answer 49

Norepinephrine and NPY

Question 50

List the current therapies for atherosclerosis

Answer 50

1) Peroxisome proliferator-activated receptor (PPAR) agonists e.g. rosiglitazone and TZDs 2) Cholesterol absorption inhibitors e.g. statins 3) AMP-activated protein kinase activator e.g. metformin 4) Nitric oxide donors e.g. diazeniumdiolates and S-nitrosothiols 5) Antioxidants e.g. Vitamine C or E

Question 51

How do PPAR agonists work

Answer 51

Decrease insulin resistance, increase HDL and have anti-inflammatory effects in vessel wall

Question 52

How do statins work

Answer 52

Increase HDL and decrease LDL levels and oxidation

Question 53

How do AMP-activated protein kinase activators work

Answer 53

Regulate glucose metabolism and increase FA oxidation

Question 54

How do nitric oxide donors work

Answer 54

They improve vasoresponsiveness

Question 55

How do antioxidants work

Answer 55

They reduce ROS and LDL oxidation

Question 56

What does A-beta promote

Answer 56

1) TNF-alpha release from macrophages 2) Endothelial cell and VSMC apoptosis 3) Monocyte migration and activation 4) MAPK signalling