Lecture 5 - cellular and molecular mechanisms of diabetes induced vascular complications Flashcards
What is atherosclerosis?
inflammatory and proliferation response to vessel wall injury
what are the three layers of an artery
Tunica intima / media / adventia
What is the progression of atherosclerosis
- Fatty streak
- Fibrous plaque
- Advanced plaque
- Complete occlusion thrombosis
What are clinical manifestations of atherosclerosis?
Cardiac –> angina / MI
Cerebral –> stroke
Peripheral –> claudication /ischaemia / ulceration
What are some cardiovascular risk factors?
Smoking / diabetes / diet / age / FH / sedentary lifestyle / alcohol / HTN / cholesterol / obesity
What are risk factors for Type II diabetes ?
ethnicity / diet / genetics / obesity / sedentary lifestyle
How do beta cells initially response to insulin resistance?
Elevate insulin levels by:
increased insulin production
increased beta cell mass
What happens when beta cells are unable to compensate
T2DM
- decreased insulin secretion
- reduced beta cell mass
- decreased pro insulin biosynthesis
What micro vascular complications of diabetes
nephropathy / neuropathy / retinopathy
What are macro vascular complications of diabetes
CHD/ PVD/ stroke
What is the role of the endothelial?
Anti-inflammatory Anti-hypertrophic Anticoagulant / prothrombolytic endothelium dependent vasodilation anti-thrombotic
What is the role of NO in the endothelium?
- dilates blood vessel
- reduces platelet stickiness
- reduces monocyte stickiness –> plaque prevention
- reduces multiplication of smooth muscle cells in the arterial wall
- reduces release of radicals
- reduces oxidation of LDL
What happens in endothelium signalling in a healthy state
PI3K pathway
- forms eNOS
- prostacyclin released
- NO released into smooth muscle cell
What is endothelial dysfunction characterised by?
impaired relaxation pro-thrombosis pro-coagulation pro-inflammation insulin resistance
What are the harmful substances that affect the endothelium
ROS/ ET/ AT-2 / EDCF
What factors influence endothelial dysfunction in diabetes?
AGEs / lipids / glucose / cytokines / insulin / HTN / oxidative stress
What increases the risk of vascular complications?
Hyperglycaemia
How is blood glucose measured and what is the healthy range
HbA1c
4-6%
What did the UKPDS:DCCT show about glycaemic control?
controls micro vascular complications but has no evidence of macrovascular benefit
what did the ACCORD; ADVANCE; VADT clinical trial show about glycaemic control?
Intensive glycaemic treatment had little, if any additional benefit in patients with diabetes and established CAD.
Early glucose control seems to be important to reduce long-term complications.
What is metabolic memory?
-sustained effects of prior glucose control
-Ongoing beneficial effects on diabetic complications
after a period of improved glycaemia followed by a
return to (often inferior) control
What clinical trials have shown evidence for metabolic memory
UKPDS-legacy effect
DCCT-metabolic memory
Describe models that have shown metabolic memory in cell culture models
Human SMC explant cultures
- fresh saphenous vein
- placed into explant culture
- Primary explants formed in 7-14days
- confluent SMC formed in 3-4 weeks
- Diabetic patients had dense / broad / disorganised SMC
- diabetic SMC was rhomboid shape rather than spindle
What are the difference in the SMC f-actin cytoskeleton between diabetics and non-diabetics?
ND–> spindle formation + elongated f-actin
T2DM –> rhomboid morphology + fragmented f-actin
What are other differences between ND SMC and T2DM SMC
- T2DM cells have a larger cell area
- T2DM cells have a poor replicating capacity
Do T2DM SMC retain their abnormal structure?
Yes
What is epigenetic change?
Change in phenotype but not a change in genotype?
What are three factors involved in epigenetic expression?
Histone modification
DNA methylation
RNA
What are miRNA
- short / single stranded non-coding RNAs
- regulate up to 50% of genes
- cell type/ tissue specific
How do miRNA affect target gene expression?
mRNA degradation
translational repression
What happens to miRNA in disease states?
+ potential use?
expression levels are modulated in a range of disease states
-targeted in new therapies
Explain miRNA synthesis
-transcribed by RNA polymerase into primary miRNA
-converted by microprocessor complex to pre-miRNA
-exported into the cytoplasm by the RAN-GTP-dependent transporter Exportin-5
- Additional processing by the Dicer enzyme produces a miRNA/miRNA
-
What occurs to miRNAs in T2DM patients?
specific miRNAs are elevated in SMC in T2DM patients
Phenotype of SMC in T2DM patients
Rhomboid
Larger spread areas
Truncated, disrupted f-actin fibres
Impaired proliferation
