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Diabetes is a chronic disease that occurs either when β-cells in pancreas do not produce enough insulin or when the body cannot effectively use the insulin it produces. Hyperglycaemia (raised blood sugar) is a common outcome of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially blood vessels, heart and nerves (12).

Type 1 diabetes

Type 1 diabetes (previously known as insulin dependent, juvenile or childhood onset diabetes) is characterized by deficient insulin production and requires daily administration of insulin. A series of functional defects in the β-cells, immune system, bone marrow and thymus collectively contribute to the pathophysiology of type 1 diabetes (615). However, it is not preventable with current knowledge.

Type 2 diabetes

Type 2 diabetes (formerly called non-insulin dependent or adult onset) is associated with insulin resistance (particularly hepatic) as well as with β-cell dysfunction (see Section 1.5)(616). T2DM comprises 90% of people with diabetes around the world (12).

1.10.1

Mechanism of CVD in diabetes

Type 2 diabetes is associated with an increased risk of premature mortality from vascular causes (617). It is estimated that people with T2DM have double the risk for an incident vascular event compared to people without T2DM (618). Diabetes leads to elevation of many cardiovascular (CV) risk factors including

hyperglycaemia, insulin resistance or deficiency, free fatty acidaemia, sympathetic stimulation, hypertension, hyperlipidaemia, and inflammation. Hyperglycaemia is also an important factor and produces tissue damage via a number of pathways, including the aldose reduction pathway, advanced glycation end product (AGE) pathway, reactive oxygen intermediate pathway, and protein kinase (PKC) pathway (619). In spite of the close association between diabetes and the development of CVD, intensive management of

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glycaemic control is only of limited benefit in decreasing CVD risk. In contrast, control of other risk factors, such as hypertension and hypercholesterolemia has marked benefits in terms of reducing rates of CVD (620). The reason that

glucose-lowering is less effective in type 2 than in type 1 for reducing CVD may actually be because lipids and BP are just as important hallmarks of the

condition as glucose, even though we diagnose it using glucose levels.

Diabetes is associated with both vascular and autonomic nervous system (ANS) dysfunction. Both these mechanisms generally co-exist in the setting of

diabetes, and also progress simultaneously. The possible interrelationship between vascular and autonomic dysfunction may also impact on the pathological process of organ damage in diabetes. Meyer et al. studied the relationship between ANS and vascular function and compared T2DM patients with controls (621). Patients with T2DM had arterial dysfunction with increased PWV, carotid intima media thickness (cIMT), and reduced systemic arterial compliance. Vascular dysfunction correlated with hyperinsulinaemia and

autonomic neuropathy as assessed by heart rate variability during breathing and postural manoeuvres (621). Similarly hypertension has been implicated as a strong risk factor for distal polyneuropathy observed in T2DM (622). Moreover treatment with ACE inhibitors has been shown to be associated with an

improvement of nerve conduction velocity in distal symmetrical polyneuropathy (623). The Atherosclerosis Risk In Communities (ARIC) study also demonstrated an independent association of impaired cardiac autonomic control with the development of ischemic heart disease among individuals with diabetes (624).

In diabetes, insulin resistance within the cardiovascular system is associated with chronic low-grade inflammation, increased oxidative stress, lipotoxicity, and activation of the RAAS (402). These conditions promote serine

phosphorylation of different insulin signalling molecules such as IRS-1 and the impairment of the normal tyrosine phosphorylation cascade (625), thus impairing insulin metabolic signalling.

1.10.1.1 Endothelial dysfunction in diabetes

Endothelial dysfunction is considered one of the important mechanisms in CV complications and is impaired from the onset of diabetes. It is still unclear

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whether endothelial dysfunction is primarily caused by diabetes or other factors (626). Proposed mechanisms for diabetes related endothelial dysfunction are as follows:

1. Hyperglycaemia leads to increased intracellular glucose concentration within ECs causing structural changes in ECs in the form of increased deposition of collagen and fibronectin. It also decreases endothelial proliferation, NO production and increased apoptosis (627;628).

2. Hyperglycaemia alters EC function indirectly by the alteration of growth and vascular factors in other cells (629)

3. Other associated metabolic alterations (dyslipidaemia, hypertension and inflammation) also cause endothelial dysfunction (630).

1.10.1.2 Diabetes induced mitochondrial dysfunction and vascular disease

Diabetes-associated hyperglycaemia affects mitochondria in ECs; mitochondrial dysfunction plays a central role in endothelial dysfunction in T2DM (631). Hyperglycemia induced mitochondrial dysfunction cause vascular dysfunction through at least three pathways: mROS production, apoptosis and damage memory.

Mitochondrial dysfunction in T2DM is evident from lower mitochondrial O2 consumption, ψm, GSH/GSSG ratio, and higher mROS production (632). Hyperglycaemia increases ROS production by the mitochondrial electron

transport chain causing vascular damage (633;634), whereas activation of AMPK reduces hyperglycaemia-induced mitochondrial ROS production and promotes mitochondrial biogenesis in ECs (635). Recently, Li et al. also showed that

endothelium-selective activation of AMPK prevents diabetes-induced impairment in vascular function and favours reendothelialization (636).

Hyperglycaemia induces EC apoptosis, and in addition to elevated mROS, mitochondrial membrane depolarization is also implicated in hyperglycaemia- induced apoptosis of human aortic ECs (637).

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The existence of persistent vascular damage and poorer CVD outcomes in people with diabetes despite apparently good glycaemic control can be regarded as a paradox. However, the average level of glycaemic control since the time of diagnosis is much more important than the current level of control: the concept of glycaemic memory can be demonstrated and appears to contribute to

prevention of CVD over long durations of follow-up (638-640). The mitochondrial ROS-driven hyperglycaemic stress is remembered in the vasculature even after glucose normalization and promotes vascular dysfunction. The mitochondrial adaptor protein p66Shc has a critical role in the hyperglycaemic memory. When EC from human aorta and aortas of diabetic mice were exposed to high glucose, the activation of p66Shc by protein kinase C β II (PKCβII) persisted even after achievement of normoglycaemia. Persistent p66Shc up regulation and

mitochondrial translocation are associated with continued ROS production, reduced NO bioavailability, and EC apoptosis. After achievement of

normoglycaemia, in vitro and in vivo gene silencing of p66Shc, blunted ROS production, restored endothelium dependent dilatation and attenuated apoptosis (641).

In summary, hyperglycaemia upregulates mROS production, impairs ROS

buffering system, damages mitochondrial DNA, alters mitochondrial membrane potential and finally impairs the balance between anti-apoptotic and pro- apoptotic pathways; all leading to endothelial and vascular dysfunction.

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Figure 1.10 The toxins and signalling pathways contributing to hyperglycaemia’s adverse effects for complications (642)

Redrawn with permission from Scott JA, Annals of the New York Academy of Sciences, 2004

Part 4