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Diabetes, Atherosclerosis, and Hyperglycemia

Cardiovascular disease (CVD) and diabetes represent two of the largest public health problems worldwide [1, 2]. More than 17 million people die from CVD every year and over 150 million have been diagnosed with diabetes [3, 4]. In Western countries and some non-Europid populations, such as Native American and Canadian communities, Pacific and Indian Ocean communities, and Australian Aboriginals [4], the prevalence of diabetes is higher than in the general population, with many more people in a “prediabetic” state [5]. Of further concern is that people with diabetes have an increased risk of CVD, leading to decreased life expectancy and quality of life [1, 4]. The World Health Organisation has reported that CVD is responsible for ca. 50% of deaths among people with diabetes [1]. Many studies have demonstrated that people with diabetes are at a 2–4-fold increased risk of CVD and mortality (reviewed in [6]). The risk of CVD always appears to be higher in people with diabetes than those without diabetes, regardless of geographical variation in risk [7].

People with diabetes manifest a number of clinical features considered to be CVD risk factors. Proatherogenic abnormalities in lipoprotein composition, subclass distribution, and lipoprotein metabolism have been identified in humans with Type 2 and Type 1 diabetes, particularly in the former where glycemic control is poor (reviewed in [8]). Notably, while the lipid profile of people with Type 1 diabetes with moderate to good glycemic control is relatively normal, the rate of CVD remains accelerated [8]. Hemostatic abnormalities indicative of hypercoagulability and increased platelet aggregation and adhesion are also demonstrable in people with diabetes (reviewed in [9, 10]). However, these abnormalities do not fully explain the increased risk of CVD.

It is widely held that the hyperglycemia in diabetes contributes to the increased incidence of atherosclerosis [10–12]. Large vessel disease appears at around the time of the first diagnosis of Type 2 diabetes, therefore hyperglycemia in the prediabetic state may be important in the development of atherosclerosis [10]. Tight hyperglycemic control has not been conclusively linked with improved macrovascular outcomes, although there are clear microvascular benefits. The Diabetes Control and Complications Trial (DCCT) demonstrated that in people with Type 1 diabetes good blood glucose control reduced the risk of retinopathy and cardiovascular events [13]. However, the numbers used in this study were small and a relatively young population was studied. A follow-up to the DCCT reported that intensive glycemic control inhibited the increases in carotid-intima thickness (a widely accepted predictor of atherosclerosis) detected in people with diabetes [14]. Glycated hemoglobin (HbA1c) concentration is an indicator of average blood glucose over the previous 3 months and may be used as a monitoring tool for diabetes [15]. The United Kingdom Prospective Diabetes Study (UKPDS) provided clear evidence that decreasing HbA1c reduced

microvascular complications, but not macrovascular disease [16]. Indeed Brownlee [12] has put forward the concept of hyperglycemic memory in which there is a persistence or progression of hyperglycemic-induced vascular complications during periods of normoglycemia.

There are many possible mechanisms as to how hyperglycemia might induce atherosclerosis. These include increased polyol pathway flux, increased advanced glycation end-product (AGE) formation, activation of protein kinase C (PKC), increased oxidative stress, and increased hexosamine pathway flux. It has been suggested that these mechanisms may have a common element of overproduction of superoxide radicals by the mitochondrial electron transport chain (reviewed in [12]).

Glycation, Glycoxidation, and the Formation

of Advanced Glycation End Products

Glycation of proteins involves reactions between a sugar, such as glucose or another reactive aldehyde, and a nucleophilic group on the protein. Thus, reaction occurs with the amine groups at the N-terminus and on Lys side chains, at the guanidine group of Arg side chains, and with the thiol group of Cys residues [17]. The extent of this spontaneous reaction is dependent on the duration of exposure to the modifying species and leads to the formation of a Schiff base (or thiohemiacetal in the case of Cys residues [18]). The Schiff bases formed with nitrogen nucleophiles undergo rearrangement to form an essentially irreversible ketoamine Amadori product [19]. Subsequent reactions of these species result in the generation of a heterogenous group of adducts collectively known as advanced glycation end products (AGE). Aldehydes such as glycolaldehyde and methyglyoxal, the levels of which are increased in diabetes (discussed later), can also glycate proteins, and the rates of reaction of these compounds are known to be significantly greater than that for glucose itself [17, 20]. Glucose and other aldehydes, whether free or protein-bound, can also undergo autoxidation reactions which yield radicals and other reactive intermediates (e.g., H2O2 and other peroxides) which can also contribute significantly to AGE generation. These latter processes are often termed glycoxidation [19, 21, 22].

Protein Glycation/Glycoxidation and AGE Accumulation

in Diabetes

Modifications to proteins brought about by glycation and glycoxidation reactions include increases in chromophores and fluorophores, modification of Arg, Cys, and Lys side chains and the N-terminus, increases in net negative charge, unfolding, cross-linking, and fragmentation [18, 20, 21, 23–26]. It has been shown that the protein fragmentation and conformational changes brought about by the reaction of proteins with glucose are dependent upon