Role of Insulin and Leptin in Vascular Disease Flashcards
List some of the key effects of insulin signalling
Anti-lipolysis (not breaking down fat), glucose internalization, glycogen synthesis, protein synthesis, anti-apoptosis and increased endothelial NO and endothelin-1 (ET-1) production
List the basic ‘insulin metabolic arm’
Insulin -> insulin receptor -> IRS-1 -> PI3K -> Akt -> eNOS
What pathway does insulin take to activate ET-1
MAPK pathway
What does eNOS stand for
Endothelial nitrous oxide synthase
What effect does NO have on the endothelium
Reduces expression of adhesion molecules in endothelium, promotes vasorelaxation and inhibits proliferation of vascular smooth muscle cells and platelets
What effect does ET-1 have on the endothelium
Increases expression of adhesion molecules, favours platelet aggregation and promotes VSMC contraction
Where are insulin receptors in blood vessels
On the endothelial and smooth muscle cells
List the 3 key ways insulin plays a key role in regulating whole body glucose disposal in the endothelium
1) Transendothelial support (insulin mediated glucose disposal)
2) Vasodilation of blood vessels (eNOS and NO production)
3) Production of hormone mediators (NO and cGMP)
List the three ways insulin acts as an anti-atherogenic in endothelial cells
1) Decreased endothelial cell apoptosis
2) Decreased ROS and increased antioxidant production
3) Reduced adhesion molecule expression
What insulin pathway promotes ANGII production
MAPK signalling
What ion can insulin change intracellularly to induce vascular relaxation
Calcium
What insulin pathway exerts an anti-apoptotic effect
PI3K
When does insulin stimulate ET-1 receptor expression
In moments of hyperinsulinaemia
What are zucker and goto-kakizaki rats
Zucker= Obese Goto-Kakizaki= Spontaneously hypertensive rats
How do zucker and goto-kakizaki rats show evidence for insulin resistant vascular disease
Both show co-existing insulin resistance and hypertension
What does genetically reduced insulin signalling in animal models show in atherosclerosis
Accelerated atherosclerosis progression
Relationship between insulin sensitivity and vasoresponsiveness
Increased insulin sensitivity results in an improved vasoresponsiveness
What three things lead to a decrease of eNOS (resulting in reduced vasodilation and subsequent endothelial dysfunction)
IL-6, TNF-Alpha and insulin resistance
What are cytokines
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
What are chemokines
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.
What are adhesion molecules
Molecules that bind to specific immune cells and promote extravasation?? Dysfunctional endothelial and VSMC overexpress adhesion moeclules in response to pro-inflammatory cytokines
What are TLRs
Toll like receptors are pro-inflammatory receptors which initiate inflammation.
What TLRs are involved in atherosclerosis
2 and 4 (expressed on endothelial cells and macrophages
What do lipids do to TLR2/4
Bind and activate them while initiating endothelial cell dysfunction and foam cell formation
What ILs do TLRs promote and how do they do this
Signal through MyD88 to promote IL-1 and 12
What does NEFA and FFA stand for
Non-estrified fatty acids and free fatty acids
What parts of the body release free fatty acids
Hypertrophic adipocytes
What can occur when you increase FFA in healthy subjects to the range of what it is in obesity and T2DM
Reduced insulin resistance, rapidly (48 hours) induces markers of endothelial activation (adhesion molecules), vascular inflammation (MPO) and thrombosis
What receptors do saturated fatty acids bind to
TLR2/4
What kinases are activated by TLR2/4
Ser/Thr kinases
What do Ser/Thr kinases phosphorylate
IRS-1 and 2 at serine residues
What do lipoproteins transport
Lipoproteins transport cholesterol from the liver to adipocytes for storage
What lipoproteins are protective against atherosclerosis and which is a risk factor for it
HDL is protective against atherosclerosis and LDL initiate vascular inflammation and damage
Why does LDL make atherosclerosis more likely when compared to HDL
LDL is more susceptible to oxidisation which in turn promotes foam cells formation
Discuss briefly oxLDL and foam cells
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
What are the two main parts of an atherosclerotic plaque
The lipid centre and fibrous cap
List all the immune cells involved in atherosclerotic plaques
Monocytes (macrophages), T and B cells, neutrophils and dendritic cells
List the key molecules of reactive oxygen species
Superoxide, hydroxyl radicals and peroxynitrite
What are ROS used for under physiological conditions
Act as signalling molecule for growth factor signalling, aerobic respiration/metabolism
What produces ROS
Ang II, cytokines and LDL
How is peroxynitrite formed and what effect does this have
Superoxide reacts with NO, reducing bioavailability of NO and NO uncoupling
Name the two negative regulators of leptin signalling
SOCS3 and PTP1B
How does exogenous leptin infusion increase arterial blood pressure
Increased endothelin-1 expression
Is STAT3 signalling protective or a risk factor for atherosclerosis
Protecting
Describe leptins actions in endothelial cells
Reduces apoptosis, promotes endothelial cell proliferation and induces NO production
Describe leptins actions in VSMCs
Stimulates migration, hypertrophy and proliferation, NO production, calcification, leptin resistance impairs vascular responsiveness, inhibits Ang-II induced calcium increasei
How does activation of the sympathetic nervous system indirectly contribute to atherosclerosis
1) Increased vasoconstriction
2) Stimulating platelet aggregation
3) Promoting insulin resistance
4) Stimulating monocyte and neutrophil production and activation
How to measure sympathetic tone
Plasma noradrenaline levels
Name the sympathetic neurotransmitters that promote proliferation and hypertrophy
Norepinephrine and NPY
List the current therapies for atherosclerosis
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
How do PPAR agonists work
Decrease insulin resistance, increase HDL and have anti-inflammatory effects in vessel wall
How do statins work
Increase HDL and decrease LDL levels and oxidation
How do AMP-activated protein kinase activators work
Regulate glucose metabolism and increase FA oxidation
How do nitric oxide donors work
They improve vasoresponsiveness
How do antioxidants work
They reduce ROS and LDL oxidation
What does A-beta promote
1) TNF-alpha release from macrophages
2) Endothelial cell and VSMC apoptosis
3) Monocyte migration and activation
4) MAPK signalling
