**2. Mechanisms by which diabetes increases cardiovascular disease**

All forms of diabetes are characterized by chronic hyperglycemia and the development of diabetes-specific macrovascular disease affecting the coronary arteries. Large prospective clinical studies show a strong correlation between hyperglycemia, insulin resistance and diabetic macrovascular complications in both type 1 and type 2 diabetes mellitus [5]. Five major molecular mechanisms have been implicated in hyperglycemia-induced tissue damage [6]: (1) increased polyol pathway flux, (2) increased advanced glycation end products (AGEs), (3) activation of protein kinase C (PKC), (4) increased hexosamine pathway flux, and (5) activation of the 12/15-lipoxygenase (12/15-LO) pathway [5]. Hyperglycemia-induced overproduction of superoxide is the causal link between high glucose concentration and the pathways responsible for hyperglycemic damage [5] (**Figure 1**).

**2.1. Increased polyol pathway flux**

oxide (NO) release and functionality [13, 14].

tion between free ε-amino or NH<sup>2</sup>

tissue damage [19, 20].

Aldose reductase (alditol:NADP+ 1-oxidoreductase) is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of glucose to sorbitol, which is further processed to fructose [7]. Aldose reductase (AR) has a low affinity (high *K*m) for glucose and, under euglycemic conditions, this pathway plays a minor role in glucose metabolism [6]. Excess glucose is also channeled into the accessory polyol pathway, where it is reduced to polyalcohol sorbitol by AR, an NADPH-dependent enzyme [8]. In the polyol pathway, sorbitol is oxidized to fructose by sorbitol dehydrogenase, with NAD+ reduced to NADH. Under hyperglycemia, this pathway can account for 25–30% of total glucose metabolism [9]. Overexpression of human AR in low-density lipoprotein (LDL) receptor (LDLR) deficient mice resulted in increased atherosclerotic lesion size if mice became diabetic by administration of streptozotocin (STZ) [5, 10]. Atherosclerotic lesions in normoglycemic LDLR−/− did not differ significantly between AR-overexpressing mice and mice with normal AR expression [11]. Long-term polyol pathway activation also increased intimal thickening in dog coronary arteries, an effect that could be blunted by AR inhibition [12]. Polyol pathway activation also triggered abnormalities in endothelium-dependent relaxation in aortas from STZ-diabetic rats and decreased nitric

Dietary Recommendations for Patients with Cardiovascular Disease and Diabetes

http://dx.doi.org/10.5772/intechopen.71391

35

**2.2. Increased intracellular formation of advanced glycation end products (AGEs)**

One of the important mechanisms responsible for accelerated atherosclerosis in diabetes is the Maillard reaction—a type of non-enzymic browning which involves the reaction of carbonyl compounds, especially reducing sugars, with compounds which possess a free amino group, such as amino acids, amines, and proteins [15]. This reaction is subdivided into three main stages. In an early stage, the protein glycation process starts with a nucleophilic addi-

reducing sugars (normally glucose or glyceraldehyde) to form a reversible Schiff base [16]. By structural irreversible rearrangements, more Amadori products—stable keto-amines—are formed (i.e., hemoglobin A1c (Hb A1c) [17]. In an intermediate stage, breakdown of Amadori products results in a variety of reactive dicarbonyl compounds such as glyoxal, methylglyoxal, and deoxyglucosones. In the late stage of glycation due to oxidation, dehydration, and cyclization reactions, irreversible compounds called AGEs are formed [18]. AGEs act either by modifying substrates, or by interacting with specific receptors [16]. AGEs-induced damage can occur to the vasculature, vascular cells, and cells implicated in vascular homeostasis via at least the following 4 mechanisms [19, 20]: (1) AGEs modify intracellular proteins, including those involved in the regulation of gene transcription; (2) precursors of AGEs leave the cells via diffusion and modify nearby extracellular matrix molecules, subsequently altering the signaling between matrix and cells and ultimately causing cellular dysfunction; (3) AGEs and their precursors modify circulating proteins in the bloodstream, thereby altering their function; (4) circulating proteins modified by AGEs bind to and activate AGE receptors, thereby altering the production of inflammatory cytokines and growth factors and causing

The deleterious effects of AGEs on the vasculature can also be classified either as follow:


**Figure 1.** Pro-atherogenic mechanisms of diabetes associated with hyperglycemia. Four hyperglycemia-related mechanisms may promote diabetic atherosclerosis: (1) the polyol pathway, (2) formation of advanced glycation end products (AGEs), (3) activation of protein kinase C (PKC) isoforms, (4) the 12/15-lipoxyenase pathway, and (5) the hexosamine pathway. All four mechanisms result in increased formation of reactive oxygen species (ROS) and promote diabetic atherosclerosis by various mechanisms as depicted in the figure. Boxes in arrows, cells and ECM indicate relevant pathway. 12/15-LO = 12-/15-lipoxygenase, AR = aldose reductase, EC = endothelial cell, ECM = extracellular matrix, Fruc = fructose, GFAT = glutamine-fructose-6-phopshate amidotransferase, Glc = glucose, Mo = monocyte, Mφ = macrophage, RAGE = receptor for advanced glycation end products, SDH = sorbitol dehydrogenase, VSMC = vascular smooth muscle cell, other abbreviations are explained in the text. Reprinted with permission from [5].
