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Diabetes and metabolic disease BMSc > Role of Insulin and Leptin in Vascular Disease > Flashcards

Role of Insulin and Leptin in Vascular Disease Flashcards

1
Q

List some of the key effects of insulin signalling

A

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

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2
Q

List the basic ‘insulin metabolic arm’

A

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

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3
Q

What pathway does insulin take to activate ET-1

A

MAPK pathway

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4
Q

What does eNOS stand for

A

Endothelial nitrous oxide synthase

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5
Q

What effect does NO have on the endothelium

A

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

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6
Q

What effect does ET-1 have on the endothelium

A

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

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7
Q

Where are insulin receptors in blood vessels

A

On the endothelial and smooth muscle cells

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8
Q

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

A

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

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9
Q

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

A

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

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10
Q

What insulin pathway promotes ANGII production

A

MAPK signalling

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11
Q

What ion can insulin change intracellularly to induce vascular relaxation

A

Calcium

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12
Q

What insulin pathway exerts an anti-apoptotic effect

A

PI3K

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13
Q

When does insulin stimulate ET-1 receptor expression

A

In moments of hyperinsulinaemia

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14
Q

What are zucker and goto-kakizaki rats

A 
Zucker= Obese
Goto-Kakizaki= Spontaneously hypertensive rats
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15
Q

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

A

Both show co-existing insulin resistance and hypertension

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16
Q

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

A

Accelerated atherosclerosis progression

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17
Q

Relationship between insulin sensitivity and vasoresponsiveness

A

Increased insulin sensitivity results in an improved vasoresponsiveness

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18
Q

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

A

IL-6, TNF-Alpha and insulin resistance

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19
Q

What are cytokines

A

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

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20
Q

What are chemokines

A

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.

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21
Q

What are adhesion molecules

A

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

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22
Q

What are TLRs

A

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

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23
Q

What TLRs are involved in atherosclerosis

A

2 and 4 (expressed on endothelial cells and macrophages

24
Q

What do lipids do to TLR2/4

A

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

25
Q

What ILs do TLRs promote and how do they do this

A

Signal through MyD88 to promote IL-1 and 12

26
Q

What does NEFA and FFA stand for

A

Non-estrified fatty acids and free fatty acids

27
Q

What parts of the body release free fatty acids

A

Hypertrophic adipocytes

28
Q

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

A

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

29
Q

What receptors do saturated fatty acids bind to

A

TLR2/4

30
Q

What kinases are activated by TLR2/4

A

Ser/Thr kinases

31
Q

What do Ser/Thr kinases phosphorylate

A

IRS-1 and 2 at serine residues

32
Q

What do lipoproteins transport

A

Lipoproteins transport cholesterol from the liver to adipocytes for storage

33
Q

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

A

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

34
Q

Why does LDL make atherosclerosis more likely when compared to HDL

A

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

35
Q

Discuss briefly oxLDL and foam cells

A

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

36
Q

What are the two main parts of an atherosclerotic plaque

A

The lipid centre and fibrous cap

37
Q

List all the immune cells involved in atherosclerotic plaques

A

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

38
Q

List the key molecules of reactive oxygen species

A

Superoxide, hydroxyl radicals and peroxynitrite

39
Q

What are ROS used for under physiological conditions

A

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

40
Q

What produces ROS

A

Ang II, cytokines and LDL

41
Q

How is peroxynitrite formed and what effect does this have

A

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

42
Q

Name the two negative regulators of leptin signalling

A

SOCS3 and PTP1B

43
Q

How does exogenous leptin infusion increase arterial blood pressure

A

Increased endothelin-1 expression

44
Q

Is STAT3 signalling protective or a risk factor for atherosclerosis

A

Protecting

45
Q

Describe leptins actions in endothelial cells

A

Reduces apoptosis, promotes endothelial cell proliferation and induces NO production

46
Q

Describe leptins actions in VSMCs

A

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

47
Q

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

A

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

48
Q

How to measure sympathetic tone

A

Plasma noradrenaline levels

49
Q

Name the sympathetic neurotransmitters that promote proliferation and hypertrophy

A

Norepinephrine and NPY

50
Q

List the current therapies for atherosclerosis

A

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

51
Q

How do PPAR agonists work

A

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

52
Q

How do statins work

A

Increase HDL and decrease LDL levels and oxidation

53
Q

How do AMP-activated protein kinase activators work

A

Regulate glucose metabolism and increase FA oxidation

54
Q

How do nitric oxide donors work

A

They improve vasoresponsiveness

55
Q

How do antioxidants work

A

They reduce ROS and LDL oxidation

56
Q

What does A-beta promote

A

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

Diabetes and metabolic disease BMSc (9 decks)

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