Physicians' Academy for Cardiovascular Education

Mechanisms underlying diabetic vascular disease

Literature - Paneni F, Beckman JA, Creager MA, Cosentino F - Eur Heart J. 2013 May 2

Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I

Paneni F, Beckman JA, Creager MA, Cosentino F.
Eur Heart J. 2013 May 2


Type 2 diabetes mellitus (DM) often remains undetected for several years. Physicians thus face the disease at an advanced stage. Vascular complications may already have occurred at that stage, such as atherosclerotic disease. Considering the increasing incidence of DM, it is important to gain better understanding of the mechanisms underlying diabetic vascular disease, to find novel approaches to prevent or halt complications. We here summarise the review (part I) that focuses on recent insights in the pathophysiology of vascular disease. Part II (Beckman et al, Eur.Heart.J 2013) addresses clinical manifestations and management strategies of patients with diabetes.

Hyperglycaemia, oxidative stress, and vascular disease

Endothelial and smooth muscle cell dysfunction are central to diabetic vasculopathy, favouring a pro-inflammatory/thrombotic state. This is due to prolonged exposure to hyperglycaemia combined with other risk factors such as arterial hypertension, dyslipidemia and genetic susceptibility.
The concept of a ‘glycaemic continuum’ can explain that the detrimental effects of glucose can already occur at glycemic levels below the threshold for diagnosis of diabetes. Early disglycaemia as a result of obesity-related insulin resistance or impaired insulin secretion induces functional and structural alterations of the vessel wall, ultimately resulting in diabetic vascular complications.
Vascular function can alter as a result of an imbalance between nitric oxide (NO) bioavailability and accumulation of reactive oxygen species (ROS). Reduced NO bioavailability was found to be a strong predictor of cardiovascular outcomes. Overproduction of ROS is seen as the causal link between high glucose levels and major biochemical pathways involved in the vascular pathogenesis in diabetes.
Protein kinase C (PKC) is one of the main sources of ROS. When activated, it induces changes in the vasculature, including altered permeability, inflammation and angiogenesis, cell growth, extracellular matrix expansion and apoptosis. PKC activation causes ROS generation. Specific targets of PKC are now gaining attention for their involvement in endothelial dysfunction as a result of ROS generation, such as the P66Shc adaptor protein, implicated in mitochondrial ROS generation and translation of oxidative signals into apoptosis.
PKC has multiple effects that contribute to vascular diabetic complications, including diminishing eNOS (endothelial NO synthase) activity and increasing production of the vasoconstrictive and platelet aggregating factor endothelin-1 (ET-1).
ROS produced in the vessel wall trigger inflammation; the transcription factor NF-κB upregulates genes encoding proteins that attract monocytes and facilitate their adhesion to the vascular endothelium, with subsequent formation of foam cells.
PKC is thought to be the upstream signalling molecule affecting these vascular mechanism in the context of hyperglycaemia. In addition, mitochondrial ROS increase advanced glycation end products (AGEs). In a hyperglycaemic environment, AGE signalling deregulates vascular homeostasis.

Insulin resistance and atherothrombosis

Insulin resistance often precedes hyperglycaemia and diabetes. Obesity plays an important role in this phenomenon. Obesity involves alterations in lipid metabolism, hormonal deregulation, oxidative stress, systemic inflammation and ectopic fat distribution. Adipose tissue is a source of inflammatory mediators and free fatty acids (FFA), and indeed obese patients with type 2 DM show increased plasma levels of inflammatory markers. FFA bind and activate toll-like receptors (TLRs) which then upregulate pro-inflammatory pathways. TLR activation also alters the function of insulin receptor substrate-1 (IRS-1), with subsequent downregulation of glucose transporter GLUT-4 and thus insulin resistance. Downregulation of this pathway is also intertwined with NO production. In combination with reduced NO synthesis, oxidation of FFA generates ROS leading to vascular inflammation and AGEs production. Increased ROS associated with insulin resistance further reduce NO bioavailability. This facilitates pro-inflammatory pathways, through increased production of inflammatory cytokines, such as TNF-α. TNF-α also stimulates the expression of C-reactive protein, which subsequently down-regulates eNOS and increases the production of adhesion molecules and ET-1.
However, observations that inflammation and macrophage activation seem to occur mostly in non-adipose tissue in obesity, now divert the focus away from the adipocentric view on insulin resistance development. Suppression of inflammation in the vasculature has been shown to prevent insulin resistance in other organs.
Mouse studies demonstrated a pivotal role for the transcription factor NF-κB in oxidative stress, vascular dysfunction and inflammation. The central role of the endothelium in obesity-induced insulin-resistance suggests that blockade of inflammation and oxidative stress may be a promising strategy for prevention of metabolic syndrome.
Changes in lipid profile further contribute to the atherogenic effect of insulin resistance.

MicroRNA and diabetic vascular disease

MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. miRs have been shown to be deregulated in diabetic patients. Recent studies have explored the mechanisms through which deregulation of miR expression may contribute to vascular disease in subjects with diabetes. Hyperglycaemia leads to increased expression of some miRs that target angiogenic factors. Some miRs are also involved in AGE-induced vascular damage or other routes to endothelial dysfunction, including impairing vascular repair capacities. These observations provide the rationale to explore a protective effect of modulation of miR expression to prevent diabetic vascular complications.

Thrombosis and coagulation

Both hyperglycemia and insulin resistance contribute to the development of a prothrombotic state, by increasing plasminogen activator inhibitor-1 (PAI-1) and fibrinogen synthesis, while less tissue plasminogen activator is produced.  
Microparticles (MPs) are circulating vesicles from various cell types following apoptosis or activation. More MPs are detected in diabetic patients, which have been shown to predict cardiovascular outcome. MPs carrying tissue factor promote thrombus formation at sites of vascular injury.
Platelet hyperreactivity further contributes to the diabetic prothrombotic state. Through several mechanisms, platelet dysfunction affects the adhesion, activation and aggregation phases of the platelet-mediated thrombosis.

Vascular hyperglycaemic memory

Evidence exists that normalisation of glycaemia fails to reduce cardiovascular burden in diabetics, although early treatment of hyperglycaemia was beneficial. The persistence of hyperglycaemic stress despite blood glucose normalisation has been termed ‘hyperglycaemic memory’. Recent insights point at activation of NF-κB as a result of transient hyperglycemias, which persists despite subsequent normalisation of glucose levels. Epigenetic changes appear responsible for this phenomenon, for instance by methylation of the promoter of the NF-κB promoter. Epigenetic changes have also been described for the P66Shc adaptor protein involved in ROS generation. These changes appear to function in a self-perpetuating way towards vascular damage, despite achievement of optimal glycemic control.

Future perspectives

Since normalisation of glycaemia does not eradicate cardiovascular risk burden, mechanism-based therapeutic strategies are needed. Inhibition of key enzymes involved in hyperglycaemia-induced vascular damage or improving insulin sensitivity may prove to be promising therapeutic strategies. miRs might also be targeted, as well as newly elucidated epigenetic changes involved in ROS-generation and inflammation, in an attempt to prevent cardiovascular complications in diabetic patients.
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Find the summary of part II of this review by Beckman et al. here