*2.2.2. Receptor-dependent effects of AGEs*

AGEs initiate diabetic micro- and macrovascular complications through the structural modification and functional alteration of the extracellular matrix proteins [30]. The receptor for AGEs (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, acting as a counter-receptor for these diverse molecules [31]. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, PKC, and mitogen-activated protein kinases (MAPKs), resulting in nuclear factor NF-kappaB activity [31]. In human diabetic atherosclerotic plaques, RAGE was demonstrated to be upregulated and its expression colocalized with inflammatory markers such as cyclooxygenase 2 and matrix metalloproteinases, particularly in macrophages at the vulnerable regions of atherosclerotic plaques [32, 33]. Administration of the soluble form of RAGE (sRAGE) could work as a decoy receptor for AGEs and might inhibit the binding of AGEs to RAGE, preventing the development and progression of atherosclerosis in animal subjects [34]. The augmented response to arterial injury in diabetes was shown to be associated with RAGE, because administration of sRAGE caused decreased neointimal expansion in hyperglycemic fatty Zucker rats [35].

#### **2.3. Activation of protein kinase C**

Protein kinase C (PKC), a multifunctional serine/threonine-specific protein kinase, plays a crucial role in many cellular functions and affects many signal transduction pathways. The AGC group is named after the protein kinase A, G, and C families that are closely related to the cAMPdependent protein kinase [36]. Twelve PKC isoforms have thus far been identified, which differ in terms of structure and substrate requirements [37]. Eight isoforms are activated by diacylglycerol (DAG) [6, 38]. Hyperglycemia can contribute to the direct and indirect production of ROS via the activation of the DAG-PKC pathway [6, 38]. Indirect PKC activation may be due to RAGE engagement or polyol pathway activation or activation of the12/15-lipoxygenase (12/15-LO) pathway [39]. Increased PKC levels associated with diabetes are found in several tissues including the aorta and the heart [40, 41]. Higher PKC activation triggers hyperglycemia-induced cardiometabolic perturbations such as changes in blood flow, basement membrane thickening, vascular permeability, angiogenesis, cell growth, and enzymatic activity alterations [42, 43]. PKC activation directly increases the permeability of albumin and other macromolecules through barriers formed by endothelial cells [44]. PKCβ1 and PKCβ<sup>2</sup> are two of the classical isoforms (α, β, and γ) of PKC [45]. Of the two isoforms, PKCβ<sup>2</sup> overexpression and activation facilitates the development of cardiac hypertrophy and fibrosis, which eventually leads to left ventricular dysfunction suggesting that PKCβ may play a central role in the development of diabetic cardiomyopathy (DCM) [46, 47]. PKCβ<sup>2</sup> activation has been implicated in diabetes-associated abnormalities via inhibition of Akt (protein kinase B)-dependent endothelial nitric eNOS activity [48]. Restoration of Akt-eNOS-NO signaling has been shown to attenuate DCM and myocardial dysfunction [49]. Quantitative immunoblotting revealed a significant increase in membrane fraction expression of PKC-β1 and -β2 in failed human hearts [50]. Among the processes induced by hyperglycemia, activation of PKC may contribute to DCM by inhibiting the metabolic actions of insulin [51]. The PKC-β inhibitor ruboxistaurin (LY333531) is a class of bisindolylmaleimide [52]. In vivo LY333531 treatment prevents excessive PKCβ<sup>2</sup> activation and attenuates cardiac diastolic dysfunction in rats with STZ-induced diabetes. LY333531 suppresses the decreased expression of myocardial NO and phosphate endothelial eNOS [53]. Peroxisome proliferatoractivated receptors gamma (PPARs-γ), could directly affect vascular function because of their expression in endothelial cells and smooth vascular muscle cells [54, 55].

#### **2.4. Increased glucose flux through the hexosamine pathway**

*2.2.1. Receptor-independent effects of AGEs*

36 Diabetes Food Plan

*2.2.2. Receptor-dependent effects of AGEs*

**2.3. Activation of protein kinase C**

H2 O2

Collagen in the blood vessel wall has a relatively long biological half-life, and with time undergoes significant non-enzymatic glycation, which may have a considerable bearing on atherosclerosis [21]. Soluble plasma proteins, such as low-density lipoprotein cholesterol (LDL-C) and immunoglobulin G (IgG), are also entrapped and covalently cross-linked by AGEs on collagen [20, 22]. Glycation of LDL-C decreases recognition of LDL-C particles by the LDL-receptor and enhances the uptake of LDL-C by a low-affinity high-capacity receptor pathway on macrophages. Decreased LDLR affinity of glycated LDL-C may result in increased oxidation of particles and may sufficiently alter their structure to render them immunogenic [23]. Glycated LDL-C is more susceptible to oxidative modification than non-glycated LDL-C. Being immunogenic, glycated LDL-C accumulates in plasma and may enhance cholesterol ester accumulation in macrophages and thus may increase the risk of atherogenic complications [23]. Glycation of apolipoprotein A1 (Apo-AI), the major protein of the protective HDL-C (high-density lipoprotein cholesterol) complex is increased in T2DM and has been shown to induce conformational changes and decreased stability of the lipid-protein interaction, as well as a reduction in the ability of the lipoprotein to self-associate [24, 25]. HDL-C glycated in vitro and Apo-AI isolated from diabetic subjects show decreased ability to activate lecithin-cholesterol acyltransferase, which drives reverse cholesterol transport by esterifying the cellular cholesterol removed by HDL-C [26, 27]. In human aortic endothelial cells, glycated and glycoxidized HDL-C induces

 formation, dampens the expression of endothelial nitric oxide synthases (eNOS) decreases NO production, promotes apoptosis associated with increased caspase 3 expression, attenuates

AGEs initiate diabetic micro- and macrovascular complications through the structural modification and functional alteration of the extracellular matrix proteins [30]. The receptor for AGEs (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, acting as a counter-receptor for these diverse molecules [31]. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, PKC, and mitogen-activated protein kinases (MAPKs), resulting in nuclear factor NF-kappaB activity [31]. In human diabetic atherosclerotic plaques, RAGE was demonstrated to be upregulated and its expression colocalized with inflammatory markers such as cyclooxygenase 2 and matrix metalloproteinases, particularly in macrophages at the vulnerable regions of atherosclerotic plaques [32, 33]. Administration of the soluble form of RAGE (sRAGE) could work as a decoy receptor for AGEs and might inhibit the binding of AGEs to RAGE, preventing the development and progression of atherosclerosis in animal subjects [34]. The augmented response to arterial injury in diabetes was shown to be associated with RAGE, because administration of sRAGE caused decreased neointimal expansion in hyperglycemic fatty Zucker rats [35].

Protein kinase C (PKC), a multifunctional serine/threonine-specific protein kinase, plays a crucial role in many cellular functions and affects many signal transduction pathways. The AGC

caspase 3 inhibition, and increases release of cytochrome c into the cytosol [28, 29].

The hexosamine biosynthesis pathway (HBP) is another side branch of glycolysis [56]. The reaction in which glucose 6-phosphate is changed to fructose 6-phosphate is catalyzed by glutamine fructose-6-phosphate amidotransferase (GFAT) [57]. The major product of HBP is UDP-N-acetylglucosamine (UDP-GlcNAc) [57]. UDP-GlcNAc regulates flux through HBP by regulating GFAT activity and is the obligatory substrate of O-GlcNAc transferase [57, 58]. Hyperglycemia stimulates the expression of PAI-1 in smooth vascular muscle cells and aortic endothelial cells. This effect is thought to be an important factor in the development of vascular disease in diabetes [59, 60]. Sp1 (a protein that in humans is encoded by the SP1 gene) was the first transcription factor identified as an O-GlcNAc modified protein [60]. It has multiple O-GlcNAc modification sites, and its phosphorylation on serine–threonine is inversely proportional to its O-GlcNAc modification [57, 61]. The glycosylated form of Sp1 seems to be more transcriptionally active than the deglycosylated form [62]. The major mechanism of glucose toxicity is the increased mitochondrial superoxide production; this event can account for the diverse manifestations in vascular cells, i.e., increased polyol pathway flux, increased AGE products, activation of PKC, and increased HBP [6, 63]. Inhibition of the rate-limiting enzyme in the conversion of glucose to GFAT blocks hyperglycemia-induced increases in the transcription of TGF-b1 and plasminogen activator inhibitor-1 [64, 65]. This pathway also plays an important role in hyperglycemia-induced and fat-induced insulin resistance [66, 67]. A prospective study examined the effect of strict blood glucose control through intravenous insulin aimed at euglycemia on the concentration of UDP-GlcNAc and UDP-GalNAc in the muscles of severely insulin resistant, uncontrolled, obese, T2DM patients [67, 68].

**4. Using food to meet dietary guidelines**

light of these findings.

**5. Dietary items**

**5.1. Dietary fiber**

Evidence-based nutrition practice guidelines are devised to guide clinicians in assisting dietitians and patients/clients in taking appropriate decisions regarding nutrition care for specific disease, or conditions in typical settings [82, 83]. The 2015–2020 US Dietary Guidelines are a critical tool for professionals to help Americans make healthy choices in their daily lives to help prevent chronic disease. It serves as the evidence-based foundation for nutrition education materials that are developed by the US Federal Government for the public [77]. Strong evidence reflects a large, high-quality, and/or consistent body of evidence. Moderate evidence reflects sufficient evidence to draw conclusions. Limited evidence reflects a small number of studies, studies of weak design or with inconsistent results, and/or limitations on the generalizability of the findings [77, 84]. The ADA uses the Create Your Plate system, which divides a plate into three sections: non-starchy vegetables (the largest section), starchy foods, and meat or meat substitutes [85]. The Harvard School of Public Health uses the Healthy Eating Pyramid, which is split into nine sections, including a base of daily exercise and weight control [86]. The LiveWell for LIFE project uses National Plates to show the ideal composition of diets in various European Union countries which are both healthy, environmentally sustainable and affordable [87]. Prospective Urban Rural Epidemiology (PURE study) is an epidemiological study carried out in 18 countries, examining associations between diet and total mortality, CVD mortality, CVD events, and non-CVD mortality. [88] The PURE study carried out between 2003 and 2009 on 153,996 adults, aged 35–70 from urban and rural communities in low, middle, and high-income households, found that elevated carbohydrate diets (74.4– 80.7% of daily calories from carbs) had a mortality hazard ratio 1.28 (1.12–1.46) times greater the median follow-up period of 7.4 years [88]. Total fat and individual types of fat were associated with lower risk of total mortality, but were not significantly associated with risk of CVD mortality [89]. Reducing saturated fatty acid intake and replacing it with carbohydrate have an adverse effect on blood lipids [88]. Global dietary guidelines should be reconsidered in

Dietary Recommendations for Patients with Cardiovascular Disease and Diabetes

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

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Dietary fiber can be classified in different ways: soluble versus insoluble based on water solubility; fermentable versus non-fermentable based on whether or not it can be fermented by the microbiota in the large intestine; and viscous versus non-viscous related to its viscosity [90]. Fruit, vegetables, and cereals are the major sources of dietary fiber. The analysis of 67 clinical trials on diets high in soluble fibers suggested that these fibers lower total cholesterol and LDL-C [91]. Water insoluble fibers remain unchanged during digestion and have no effect unless they displace foods supplying saturated fats and cholesterol [92]. Most of the available epidemiologic studies suggest that dietary fiber is inversely related to coronary artery disease [93]. Diet rich in dietary fiber is beneficial for the treatment of T2DM [94], as dietary fiber ameliorates postprandial hyperglycemia by delaying digestion and absorption of carbohydrates [95]. A recent systematic review of the literature reported that moderate

#### **2.5. 12/15-lipoxygenase (12/15-LO) pathway**

12/15-LOs are enzymes that insert molecular oxygen into polyunsaturated fatty acids, such as arachidonic acids, leading to formation of 12(S)- and 15(S)-hydroxyeicosatetraeonic acid [69]. 12/15-LO enzymes and their products, namely HETEs (hydroxyeicosatetraeonic acid) and hydroxyoctadecadienoic acids, have been implicated in the pathogenesis of atherosclerosis [70]. Several studies have shown that the 12/15-LO pathway is also able to mediate oxidative modification of LDL-C [71, 72]. 12/15-LO seems to be involved in hyperglycemia, as well as minimally modified LDL-mediated adhesion of monocytes to the endothelium and promotes smooth vascular muscle cell hypertrophy [73]. Also 12(S)- HETE promotes monocyte adhesion to endothelial cells, probably in part by inducing the fibronectin splice variant CS-1 (C-terminal fragment of the connecting segment 1) and VCAM-1 on endothelial cells [73]. Some metabolites of the 12/15-LO system, i.e., 13-hydroxyoctadecadieonic acid (13-HODE) reduces platelet adhesion to endothelial cells and binds to PPARγ thereby reducing macrophage expression of matrix metallopeptidase 9 and proinflammatory cytokines [74].
