Cellular and Molecular Mechanisms of Diabetes Induced Vascular Complications - Extra Reading

Question 1

Roberts, Diabetes and Vascular Research, 2013

Answer 1

Disrupted endothelial function is an early event in the development of CVD

• In addition to its role in glucose homeostasis, insulin is needed to activate cell signalling pathways that maintain healthy endothelium
• Insulin activates the most vasoprotective pathway, the P13K pathway which enhances eNOS activity to produce more NO
• In health, the P13K vasoprotective pathway and MAPK vasoconstrictive pathway are balanced
• Because there is a deficiency of the P13K in T2DM and MAPK predominates, hyperinsulinaemia is initiated to try and restore the loss of P13K. However, this just results in further stimulation of MAPK - THIS HAS BEEN DEMONSTRATED IN OBESE ZUCKER RATS

PROBLEMS WITH OXIDATIVE STRESS

• ROS destroy NO
• and ROS uncouples eNOS from its co-factor causing it to produce more ROS than NO
• Experimental evidence has shown that ROS is an endogenous down-regulator of the P13K pathway
• In glucose toxicity, mitochondria also produce excess ROS which adds to the insult of reduced NO
• In vitro antioxidant therapies show an improvement in NO-mediated vasodilation as it reduces ROS, however clinical trials have shown no benefit of antioxidant therapies, perhaps because the effects of antioxidants are too short term to have an effect on mortality

HOW IS DNA METHYLATION IMPLICATED IN EPIGENETIC MODIFICATION IN DIABETES?

• high fat feeding of obese rats has been shown to induce hypermethylation of particular genes resulting in the diabetic phenotype and its complications
• this means it is reasonable that mechanisms similar to this also occur in humans

DIABETES THERAPIES

• Metformin is the only current therapy with the capability to reduce cardiovascular risk
• trials such as UKPDS and DCCT highlight the importance of early glycaemic control to reduce vascular complications as a result of metabolic memory
• manipulation of epigenetic modification mechanisms may provide novel therapeutic avenues

Question 2

Reddy, Cardiovascular Res, 2011

Answer 2

-there is limited research into DNA methylation in DM
-studies of mice have shown that regulation of the agouti gene by DNA methylation plays an important role in the development of obesity and diabetes
-the role of DNA methylation in CVD is not properly understood
HOWEVER
the risk of CVD and diabetes increases with age, and ageing is associated with HYPOmethylation of genomic DNA
-so perhaps if methylation could be maintained, we could lower the risk of developing CVD and diabetes

Question 3

Madi, Cell Physiology, 2009

Answer 3

• individuals with T2DM are at increased risk of saphenous vein graft stenosis due to intimal hyperplasia (25% of revascularisation patients have T2DM)
• SMCs differ from healthy in that they exhibit a rhomboid shape and larger surface area compared with a healthy spindle shape
• Growth factors, cytokines, matrixmetalloproteases, P13K and MAPK pathways trigger intimal hyperplasia by SMC proliferation that results in vessel stenosis

Question 4

Porter, Clinical Science, 2013

Answer 4

• Endothelial function declines naturally with ageing but T2DM accelerates it
• UKPDS study followed a group with early tight glycaemic control and this showed a reduction in cardiovascular events
• Modest benefits of tight glycaemic control were also seen in the ACCORD and ADVANCE trials after 5 years of follow up
• The DCCT study shows evidence of protection from macrovascular complications with tight glycaemic control 12 years after the study -however this was conducted in T1DM patients and so may not demonstrate the same outcomes as T2DM
• Reduced NO bioavailability is observed before the onset of atherosclerotic structural changes and has been shown to predict onset of CAD-so the P13K pathway is implicated before atherosclerosis and CAD occurs-if we could maintain NO availability, we may be able to prevent complications
• Rat carotid-injury models have shown that SMCs become injured, de-differentiate to become synthetic, and then once healing occurs the SMCs re-differentiate to become contractile cells again. So the cells do have the ability to re-differentiate. Why don’t they do this in diabetes then? Could be because of the metabolic memory
• Diabetic mice with atherosclerotic lesions show presence of both contractile and synthetic SMCs, so not all of the SMCs will de-differentiate (some remain normal) - it is therefore the RELATIVE PROPORTIONS of each SMC phenotype that is critical in determining vascular function

CURRENT DIABETIC THERAPEUTICS:

• Some cardiovascular therapies are reported to influence SMC phenotype, at least to some degree
  1. STATINS
• reportedly impair SMC phenotypic differentiation from contractile to synthetic and the anti-proliferative effect of statins on SMCs improves Saphenous Vein bypass grafts, HOWEVER the coral study indicated that high doses of statins impairs glycaemic control
  2. ANGIOTENSIN RECEPTOR BLOCKERS
• block angiotensin II and thus prevent SMC dedifferentiation in atherosclerotic lesions

CONCLUSION:

• there is emerging support for a distinct and persistent vascular phenotype that occurs in T2DM
• properly defining this phenotype will be valuable in identifying new therapeutic targets