The Protective Effect of Antioxidants Consumption on Diabetes and Vascular Complications

Obesity and diabetes is generally accompanied by a chronic state of oxidative stress, disequilibrium in the redox balance, implicated in the development and progression of complications such as micro- and macro-angiopathies. Disorders in the inner layer of blood vessels, the endothelium, play an early and critical role in the development of these complications. Blunted endothelium-dependent relaxation and/or contractions are quietly associated to oxidative stress. Thus, preserving endothelial function and oxidative stress seems to be an optimization strategy in the prevention of vascular complications associated with diabetes. Diet is a major lifestyle factor that can greatly influence the incidence and the progression of type 2 diabetes and cardiovascular complications. The notion that foods not only provide basic nutrition but can also prevent diseases and ensure good health and longevity is now attained greater prominence. Some dietary and lifestyle modifications associated to antioxidative supply could be an effective prophylactic means to fight against oxidative stress in diabesity and complications. A significant benefit of phytochemicals (polyphenols in wine, grape, teas), vitamins (ascorbate, tocopherol), minerals (selenium, magnesium), and fruits and vegetables in foods is thought to be capable of scavenging free radicals, lowering the incidence of chronic diseases. In this review, we discuss the role of oxidative stress in diabetes and complications, highlight the endothelial dysfunction, and examine the impact of antioxidant foods, plants, fruits, and vegetables, currently used medication with antioxidant properties, in relation to the development and progression of diabetes and cardiovascular complications.


Introduction
Today, WHO and IDF (International Diabetes Federation) draws attention to the similarity of trends in obesity and diabetes in the World. The term "diabesity" is commonly used today to describe this epidemic or pandemic with exponential dramatic growth observed in all countries [1]. Our change of lifestyle to a sedentary attitude and massive industrialization with access from an early age to food and beverages rich in energy, fat, sugar, or a combination thereof is partly the cause of millions of obese and diabetic people [2]. Despite technical and technological progress accompanying therapeutic arsenal available and public health plans, we fail today to stop the progression of diabetes and its complications. In fact, diabetes is a silent and sneaky disease. Therefore, it is associated with many complications. Cardiovascular diseases are the major cause of death and disability among diabetic people [3], particularly for woman who have lost cardiovascular protection afforded by the classically female sex. Diabetic vascular complications are an important pathological issue in diabetes that leads to the further functional deterioration of several organs and caused micro-and macro-angiopathy [4]. Endothelial dysfunction, the loss of a balance between vasodilators and vasoconstrictors factors in the blood vessels, has largely been associated in several regions of the vasculature in T2D [5].

Oxidative Stress and Cardiovascular Complications
The concept that oxygen, which is essential to life, could be causing cell damage and involved in many diseases, was discovered in recent years. Today, many epidemiological and clinical studies strongly suggest the involvement of reactive oxygen species (ROS) in the genesis and evolution of chronic diseases, including diabetes and its complications [7] (Figure 1). Chronic hyperglycemia caused a major oxidative stress [22], and Yubero-Serrano et al. [46] recently proposed SOD activity as the most relevant oxidative stress biomarker in patients suffering from metabolic syndrome. It could be used as a predictive tool to determine the degree of the underlying oxidative stress in this pathology.

Oxygen Paradox and Anti-Oxygen
Oxygen, which first appeared three billion years ago in Earth's atmosphere, is an essential molecule for life. Through redox mechanisms, oxygen, the final electron acceptor, is transformed into water by the mitochondrial respiratory chain [41]. This reaction is a source of energy through ATP production and also the formation of 2% to 3% of reactive oxygen species (ROS), a free radical that is particularly unstable and reactive [42]. In 1954, Gerschman published the free radical theory of oxygen toxicity, due to partially reduced forms of oxygen [47], and, two years after, Harman proposed the concept of involving free radicals in the aging process [48]. Whereas McCord and Fridovich discovered the enzyme superoxide dismutase (SOD) in 1969 [49] and provided convincing evidence about the importance of free radicals in the living system [50], the concept of anti-oxidants has been reported for much longer by Dufraisse and Moureu in the 1920s, when they discovered that the polymerization of acrolein was inhibited by hydroquinone, an oxygen-dependent mechanism [51]. Originally named "anti-oxygen," the Anglo-Saxon term "antioxidant" was quickly privileged and replaced. Since the properties as second messengers of ROS were discovered for the first time by Mittal and Murad in 1977 [52], many studies are now interested in this delicate balance between the beneficial and harmful effects of free radicals, which is the redox regulation for maintaining redox homeostasis and has provided protection to living organisms from various oxidative stresses.

Oxygen Paradox and Anti-Oxygen
Oxygen, which first appeared three billion years ago in Earth's atmosphere, is an essential molecule for life. Through redox mechanisms, oxygen, the final electron acceptor, is transformed into water by the mitochondrial respiratory chain [41]. This reaction is a source of energy through ATP production and also the formation of 2% to 3% of reactive oxygen species (ROS), a free radical that is particularly unstable and reactive [42]. In 1954, Gerschman published the free radical theory of oxygen toxicity, due to partially reduced forms of oxygen [47], and, two years after, Harman proposed the concept of involving free radicals in the aging process [48]. Whereas McCord and Fridovich discovered the enzyme superoxide dismutase (SOD) in 1969 [49] and provided convincing evidence about the importance of free radicals in the living system [50], the concept of anti-oxidants has been reported for much longer by Dufraisse and Moureu in the 1920s, when they discovered that the polymerization of acrolein was inhibited by hydroquinone, an oxygen-dependent mechanism [51]. Originally named "anti-oxygen," the Anglo-Saxon term "antioxidant" was quickly privileged and replaced. Since the properties as second messengers of ROS were discovered for the first time by Mittal and Murad in 1977 [52], many studies are now interested in this delicate balance between the beneficial and harmful effects of free radicals, which is the redox regulation for maintaining redox homeostasis and has provided protection to living organisms from various oxidative stresses.

Free Radicals, Oxidative Stress, and Diabetes
Beside physiological oxidations, many environmental processes have induced free radical formations: air pollutants [53], tobacco [54], UV radiation from sun [55], and industrialized lifestyle [56]. Different endogenous enzymes can also form free radicals at physiological concentrations: NADPH oxidase, xanthine oxidase, cyclo-oxygenases (COXs), and lipo-oxygenases (LPOs), nitric-oxide synthases (NOS), P450 cytochrome, and mitochondrial chain [57]. These free radical were reduced by the first line of antioxidant defense: the superoxide dismutase SOD [58]. Free radicals include reactive nitrogen species (RNS) and reactive oxygen species (ROS). The most important is superoxide anion (O 2 .´) , which is rapidly dismutated into oxygen and hydrogen peroxide ( of glucose-induced ROS production in the vasculature [65,66], kidney [65], liver [66,67], and β cells [68], confirming this enzyme as a mediator of diabetic complications. Recently, Brandes et al. [69] described molecular mechanisms of Nox activation and supported their implications in diabetes, hyperglycemia, and hyperinsulinemia through complex pathways involving NADPH oxidases. Xanthine oxidase is also implicated in diabetes and vascular complications [70], whereas treatment of T2D patients with Allopurinol, a XO inhibitor, reduces the level of oxidized lipids in plasma and improves blood flow [70]. Glucose itself, as well as its metabolites, is known to react with hydrogen peroxide in the presence of iron and copper ions to form hydroxyl radical during auto-oxidation, described in diabetes and complications by Wolff and Dean in 1987 ( Figure 2).

Antioxidants Defenses
The body has a number of very effective antioxidant defense systems to lower the concentration of free radicals in the body. The term antioxidant refers to "any substance that, when present at low concentration compared with that of an oxidizable substrate, significantly delays or inhibits oxidation of the substrate" [71]. Nature of the antioxidant systems differs depending on the cell types, tissues, and localization in the intracellular or extracellular medium [72]. There are different types of molecules, natural or synthetic, with enzymatic or scavenging activities ( Figure 3). In diabetes, the alteration of the first sites in the mitochondrial membrane lead to the activation of the complex II [59] and contribute to the formation of excessive O 2 .´b y a leakage of electrons [60].
NADPH oxidases (Nox's), a family of enzymes with the sole function of producing ROS, are implicated in the pathophysiology of many cardiovascular diseases [61][62][63][64] and are the major source of glucose-induced ROS production in the vasculature [65,66], kidney [65], liver [66,67], and β cells [68], confirming this enzyme as a mediator of diabetic complications. Recently, Brandes et al. [69] described molecular mechanisms of Nox activation and supported their implications in diabetes, hyperglycemia, and hyperinsulinemia through complex pathways involving NADPH oxidases. Xanthine oxidase is also implicated in diabetes and vascular complications [70], whereas treatment of T2D patients with Allopurinol, a XO inhibitor, reduces the level of oxidized lipids in plasma and improves blood flow [70]. Glucose itself, as well as its metabolites, is known to react with hydrogen peroxide in the presence of iron and copper ions to form hydroxyl radical during auto-oxidation, described in diabetes and complications by Wolff and Dean in 1987 ( Figure 2).

Antioxidants Defenses
The body has a number of very effective antioxidant defense systems to lower the concentration of free radicals in the body. The term antioxidant refers to "any substance that, when present at low concentration compared with that of an oxidizable substrate, significantly delays or inhibits oxidation of the substrate" [71]. Nature of the antioxidant systems differs depending on the cell types, tissues, and localization in the intracellular or extracellular medium [72]. There are different types of molecules, natural or synthetic, with enzymatic or scavenging activities ( Figure 3). The first line of defenses against free radicals groups these enzymatic systems (SOD, CAT, GPx) (Figures 2 and 3) and are aided by micronutrients (copper, zinc, selenium) [73] as cofactors. There are three isoforms for the SOD described in mammals [74]: the manganese-SOD (MnSOD) in the mitochondria, copper (Cu), or zinc (Zn) in the cytoplasm and the mitochondria, and both Cu/Zn extracellular SOD (Cu/Zn SOD) in vessels. CAT is essentially present in peroxisomes and in erythrocytes [75]. GPx is present in the extracellular fluid (blood) and in the cytoplasm and membranes of cells [76] and forms a couple with glutathione reductase (GR) providing glutathione (GSH) bioavailability [7].
The second line of defenses involves non-enzymatic antioxidants, such as naturally nutrients provided by food, with a scavenging effect (capture of free electron and formation of more stable entities), a stimulatory effect on endogenous antioxidant enzymes, or both [77]. Main molecules are GSH, vitamin E (the most active form: α-tocopherol), vitamin C (L-ascorbic acid), vitamin A (carotenoids), but also polyunsaturated fatty acids or exogenous flavonoids (quercetin, rutin, resveratrol, etc.), which can strengthen the antioxidant defenses of the body [73]. For example, increasing concentration of GSH with these products can protect against cancer [78] and diabetic complications [79]. Vitamin E traps organic free radicals from the oxidation of lipids and helps reduce lipid peroxidation.
Β-cells are particularly sensitive to ROS because they are low in free radical quenching (antioxidant) enzymes such as CAT, SOD, and GPx [80][81][82] and have a lower level of GSH [82,83]. However, the balance between free radicals and antioxidant defense systems is crucial to maintaining homeostasis; if its equilibrium is broken in favor of the pro-oxidant entities, pathological oxidative stress appears [84] (Figure 4). The first line of defenses against free radicals groups these enzymatic systems (SOD, CAT, GPx) (Figures 2 and 3) and are aided by micronutrients (copper, zinc, selenium) [73] as cofactors. There are three isoforms for the SOD described in mammals [74]: the manganese-SOD (MnSOD) in the mitochondria, copper (Cu), or zinc (Zn) in the cytoplasm and the mitochondria, and both Cu/Zn extracellular SOD (Cu/Zn SOD) in vessels. CAT is essentially present in peroxisomes and in erythrocytes [75]. GPx is present in the extracellular fluid (blood) and in the cytoplasm and membranes of cells [76] and forms a couple with glutathione reductase (GR) providing glutathione (GSH) bioavailability [7].
The second line of defenses involves non-enzymatic antioxidants, such as naturally nutrients provided by food, with a scavenging effect (capture of free electron and formation of more stable entities), a stimulatory effect on endogenous antioxidant enzymes, or both [77]. Main molecules are GSH, vitamin E (the most active form: α-tocopherol), vitamin C (L-ascorbic acid), vitamin A (carotenoids), but also polyunsaturated fatty acids or exogenous flavonoids (quercetin, rutin, resveratrol, etc.), which can strengthen the antioxidant defenses of the body [73]. For example, increasing concentration of GSH with these products can protect against cancer [78] and diabetic complications [79]. Vitamin E traps organic free radicals from the oxidation of lipids and helps reduce lipid peroxidation.
B-cells are particularly sensitive to ROS because they are low in free radical quenching (antioxidant) enzymes such as CAT, SOD, and GPx [80][81][82] and have a lower level of GSH [82,83]. However, the balance between free radicals and antioxidant defense systems is crucial to maintaining homeostasis; if its equilibrium is broken in favor of the pro-oxidant entities, pathological oxidative stress appears [84] (Figure 4).

Free Radicals: Good and Bad Boys?
ROS and RNS are well recognized for playing a dual role as both deleterious and beneficial species, since they can be either harmful or beneficial to living systems [85], but it is a well-known feature that cells are capable of generating endogenously and constitutively ROS [6].

Physiological Roles: The Good Boy Side
Oxygen homeostasis at the tissue level is vital for development, growth, and survival, and cells hence have evolved a number of mechanisms to sense and respond to low oxygen levels. Under physiological conditions, beneficial effects of free radicals occur at low or moderate concentrations and involve physiological roles in the regulation of cellular signals implicated in proliferation and cell adhesion, apoptosis, inflammatory responses, and the regulation of transcription factors [6]. ROS, in low concentration, are generating when cells are stimulated by cytokines, growth factors, and hormones [86], and ROS can thus play a role as a secondary messengers [87,88] like the mitogenactivated protein kinase (MAPK) pathways [89], probably the most significant effect of metals and ROS. This involves the activation of nuclear transcription factors and control of the expression of protective genes that repair damaged DNA, power the immune system, arrest the proliferation of damaged cells, and induce apoptosis [89]. Cell adhesion plays an important role in embryogenesis, cell growth, differentiation, wound repair, and others, depending on redox regulation [90] and the involvement of NADPH oxidase [91]. In an inflammatory environment, activated neutrophils and macrophages produce a large quantity of ROS via NADPH oxidase and myeloperoxidase. This "oxidative burst" plays a key role in the defense against environmental pathogens [92]. Low and moderate levels of ROS also play important roles in regulating autophagy and apoptosis, therefore controlling cell death and survival [93,94], and ROS generated during ischemic preconditioning (alternation of short periods of ischemia and reperfusion) confer cardiac protection by reducing necrosis and the severity of arrhythmias, improving functional recovery when challenged with a longer period of ischemia [95]. This mechanism is very complex and involves triggers, mediators, and multiple second messengers' pathways [96][97][98], but it is an innate physiologic adaptive process against potentially lethal ischemic injury. NO stimulates soluble guanylyl cyclase, leading to the relaxation of vascular smooth muscle [99] and the essential role of NO in endothelium-induced relaxation was discovered by Furchgott and Zawadzki in 1980 [100]. Nowadays, various studies report a pivotal role of NO on vascular homeostasis (anti-thrombotic, anti-aggregate, anti-migration, and relaxation) [101][102][103]. ROS play a crucial role in the activation of mechanotransduction signaling pathways and in cardiac contraction and relaxation [104]. In addition, in cardiovascular health, insulin sensitivity plays a vital role, and ROS intervene in the insulin signaling pathway. H2O2 induces typical metabolic actions of insulin, linking ROS to insulin [105], increases glucose uptake in adipocytes and muscles [106], is involved in the modulation of vascular endothelial function [107],

Free Radicals: Good and Bad Boys?
ROS and RNS are well recognized for playing a dual role as both deleterious and beneficial species, since they can be either harmful or beneficial to living systems [85], but it is a well-known feature that cells are capable of generating endogenously and constitutively ROS [6].

Physiological Roles: The Good Boy Side
Oxygen homeostasis at the tissue level is vital for development, growth, and survival, and cells hence have evolved a number of mechanisms to sense and respond to low oxygen levels. Under physiological conditions, beneficial effects of free radicals occur at low or moderate concentrations and involve physiological roles in the regulation of cellular signals implicated in proliferation and cell adhesion, apoptosis, inflammatory responses, and the regulation of transcription factors [6]. ROS, in low concentration, are generating when cells are stimulated by cytokines, growth factors, and hormones [86], and ROS can thus play a role as a secondary messengers [87,88] like the mitogen-activated protein kinase (MAPK) pathways [89], probably the most significant effect of metals and ROS. This involves the activation of nuclear transcription factors and control of the expression of protective genes that repair damaged DNA, power the immune system, arrest the proliferation of damaged cells, and induce apoptosis [89]. Cell adhesion plays an important role in embryogenesis, cell growth, differentiation, wound repair, and others, depending on redox regulation [90] and the involvement of NADPH oxidase [91]. In an inflammatory environment, activated neutrophils and macrophages produce a large quantity of ROS via NADPH oxidase and myeloperoxidase. This "oxidative burst" plays a key role in the defense against environmental pathogens [92]. Low and moderate levels of ROS also play important roles in regulating autophagy and apoptosis, therefore controlling cell death and survival [93,94], and ROS generated during ischemic preconditioning (alternation of short periods of ischemia and reperfusion) confer cardiac protection by reducing necrosis and the severity of arrhythmias, improving functional recovery when challenged with a longer period of ischemia [95]. This mechanism is very complex and involves triggers, mediators, and multiple second messengers' pathways [96][97][98], but it is an innate physiologic adaptive process against potentially lethal ischemic injury. NO stimulates soluble guanylyl cyclase, leading to the relaxation of vascular smooth muscle [99] and the essential role of NO in endothelium-induced relaxation was discovered by Furchgott and Zawadzki in 1980 [100]. Nowadays, various studies report a pivotal role of NO on vascular homeostasis (anti-thrombotic, anti-aggregate, anti-migration, and relaxation) [101][102][103]. ROS play a crucial role in the activation of mechanotransduction signaling pathways and in cardiac contraction and relaxation [104]. In addition, in cardiovascular health, insulin sensitivity plays a vital role, and ROS intervene in the insulin signaling pathway. H 2 O 2 induces typical metabolic actions of insulin, linking ROS to insulin [105], increases glucose uptake in adipocytes and Diseases 2016, 4, 24 9 of 51 muscles [106], is involved in the modulation of vascular endothelial function [107], and stimulates GLUT4 translocation and lipids synthesis in adipocytes [108]. However, ROS levels are the major determinants of impaired versus enhanced insulin sensitivity [109] through a ROS-induced increase in PI3K/Akt signaling [110].

Pathological Roles: The Bad Boy Side
Certainly necessary in many physiological pathways, their excessive production causes direct damage to biological molecules (DNA oxidation, proteins, lipids, and carbohydrates) as well as secondary damage due to cytotoxic and mutagenic character of metabolites released in particular during the lipid oxidation (Figures 2 and 5). The body may also react against these abnormal compounds by producing antibodies, which unfortunately may be autoantibodies creating a third wave of attack.

Oxidative Stress, Diabetes, and Vascular Complications
Increased oxidative stress has been proposed to be one of the major causes of hyperglycemiainduced triggers of diabetic complications, implicates several mechanisms [125], and is a bipolar process. The first is the generation of ROS, and the second is a decrease in plasma antioxidants such as vitamin E, vitamin C, lipoic acid, and glutathione [126]. Both have been observed in diabetic patients [127,128] with micro-and macrovascular diabetic complications [3,129], linking metabolicgenerated ROS to the development of diabetic complications [24]. This role of hyperglycemia has been established by large-scale prospective studies for both T1D and T2D, the DCCT/EDIC (Diabetes Control and Complications Trial) [130], the UKPDS (UK Prospective Diabetes Study) [131], and the Steno-2 study [132]. Diabetic cardiovascular complications appear to be multifactorial in origin [133,134], but, in particular, glycol-oxidative stress has been suggested to be the unifying link between the various molecular disorders in diabetes mellitus [59,135]. In fact, it is well established that hyperglycemia and acute glucose fluctuations have many side effects: modifying the redox balance, increasing circulating FFA, increasing NADPH oxidase activity and TNFα [126], and decreasing NADPH levels and glutathione, all of which generate by-products, activate oxidative, and inflammatory signaling. Hyperglycemia induces (1) an increase in glucose and other sugar fluxes While DNA is the memory of all the biochemical live composition, it is very sensitive to free radical "attack." At the very least, five main classes of oxidative damage mediated by OH‚ can be generated. Among them are oxidized bases, abasic sites, intra-catenary adducts, strand breaks, and DNA-protein bridges [111]. In addition to ROS, RNS such as peroxynitrites and nitric oxide have also been implicated in DNA damage [112]. The most extensively studied DNA lesion is the formation of 8-OH-G, and these changes are the first steps of carcinogenesis [85]; it is no coincidence that the carcinogenic agents are powerful free radical generators (UV and ionizing radiation, smoke, alcohol, asbestos fibers, carcinogenic metals, polycyclic hydrocarbons, etc.) ( Figure 5).
The carbon reactive compounds (RCCs), such as malondialdehyde (MDA) and 4-hydroxynonenal (2-HNE), are formed endogenously during lipid peroxidation and glycoxidation of carbohydrates. They react with the tissue and cellular proteins to form AGEs (advanced glycation end-products) and ALEs (advanced lipid peroxidation end-products), inducing protein dysfunctions (loss of activity, increased sensitivity to proteases) [113,114] and damage in cellular responses-in particular, in inflammatory responses and apoptosis [114,115]. Lipids, mainly polyunsaturated fatty acids, are the main target of the attack by OH‚ and form conjugated diene radical [116]. These modifications concern circulating lipoproteins or membrane phospholipids. These derivatives are often hydrophobic and will therefore form in and around abnormal clusters of endothelial cells. These RCCs, MDA, 4-HNE, or oxidized-LDL were found in large quantities during mechanisms of carcinogenesis in various stages of cardiovascular diseases [117] such as atherosclerosis [118,119], metabolic syndrome [7], diabetes and complications [120], obesity, and insulin resistance [121], and in chronic inflammatory diseases such as lupus [122], asthma, chronic inflammation of the lungs, and respiratory allergies [123,124], and in degenerative diseases [120] ( Figure 5).

Oxidative Stress, Diabetes, and Vascular Complications
Increased oxidative stress has been proposed to be one of the major causes of hyperglycemia-induced triggers of diabetic complications, implicates several mechanisms [125], and is a bipolar process. The first is the generation of ROS, and the second is a decrease in plasma antioxidants such as vitamin E, vitamin C, lipoic acid, and glutathione [126]. Both have been observed in diabetic patients [127,128] with micro-and macrovascular diabetic complications [3,129], linking metabolic-generated ROS to the development of diabetic complications [24]. This role of hyperglycemia has been established by large-scale prospective studies for both T1D and T2D, the DCCT/EDIC (Diabetes Control and Complications Trial) [130], the UKPDS (UK Prospective Diabetes Study) [131], and the Steno-2 study [132]. Diabetic cardiovascular complications appear to be multifactorial in origin [133,134], but, in particular, glycol-oxidative stress has been suggested to be the unifying link between the various molecular disorders in diabetes mellitus [59,135]. In fact, it is well established that hyperglycemia and acute glucose fluctuations have many side effects: modifying the redox balance, increasing circulating FFA, increasing NADPH oxidase activity and TNFα [126], and decreasing NADPH levels and glutathione, all of which generate by-products, activate oxidative, and inflammatory signaling. Hyperglycemia induces (1) an increase in glucose and other sugar fluxes through the polyol pathway, (2) an increase in advanced-glycation end-products (AGEs) formation through the hexosamine pathway, (3) expression of their receptor (RAGE) [136], and (4) the stimulation of protein kinase C (PKC) pathway. These mechanisms lead to increase production of glycative, glycoxidative, and carbonyl free radicals [22,137,138], which altered enzymatic and non-enzymatic antioxidant defenses. For example, oxidative stress increases mitochondrial DNA damages and causes axons cell death, leading to neuropathies [139]. Accumulation of sorbitol, due to an enzymatic conversion of excessive glucose, disrupts osmotic balance [140], a higher fructose production induces AGEs formation [141], and all participate in peripheral insulin resistance development [142,143] and β-cells injury [144]. Elevated AGEs may be a significant risk factor for T1D [145] and induce the progression of pre-diabetes to diabetes [146] and some complications such as diabetic retinopathy [147]. As shown before, oxidative stress is closely link to inflammation. Indeed, circulating TNF-α may impair vascular function by altering the balance between endothelial-derived vasodilator and vasoconstrictor substances because it downregulated the expression of eNOS and upregulated ET-1 production in endothelial cells [148]. Moreover, it may also directly activate NADPH oxidase and then increase the production of ROS in the vasculature [149].
Oxidative stress can be measured in vivo in multiple types including cells, solid tissues, urine, blood, and saliva. Several investigations correlated oxidative stress observed in serum and in saliva, and, today, saliva can be considerate as an oxidative stress diagnostic fluid [150,151]. Some human studies highlight reactive compounds in saliva in some pathologies, such as T1D [152][153][154][155] and T2D [153,156], with the detection of biomarkers such as 8-oxodG [152], MDA, and TBARS, proteins carbonyl [152], and total antioxidant capacity [153][154][155][156]. Recently, Wang et al. published a critical review of salivary biomarkers of oxidative stress [157], highlighting the problem of standardization in methods of saliva collection and measurements of composition. They proposed a guideline that could assist in discovery and validation of salivary oxidative stress biomarkers, allowing a diagnosis or even a simple predictive test of diabetes.

Endothelial Dysfunction, Diabetes, and Complications
As shown before, a large amount of evidence has demonstrated that hyperglycemia plays an important role in the pathogenesis of microvascular complications [158]. Dysfunction of the vascular endothelium is also regarded as an important factor [159,160], closely related to hyperglycemia and more recently to hypoglycemia [161], and has gained increasing attention in the study of vascular disease [162,163]. In fact, the endothelium is in constant interaction with the blood and subjected to mechanical stresses in the vessel, namely, intraluminal pressure, variations of flow including shear stress, and high glucose concentration. This strategical localization allows it a protective role as a detector toward theses stimuli. Endothelial cells respond to them through the production of messengers, addressed to cells by the blood. Thus, the endothelium plays a key role in vascular homeostasis by regulating the balance between relaxing and contracting factors. However, this protective role of the endothelium is also the first target of risk factors such as high cholesterol or high blood pressure [164], smoking [165], obesity and visceral fat distribution [166], impaired fasting glucose and hyperglycemia [167,168], insulin resistance [169][170][171][172] where this strategic balance is lost in favor to pro-mitogenic, pro-aggregation mediators [173,174], and inflammation [175]. Inflammation, in addition to oxidative stress, cause injury in cells (e.g., endothelial cells), leading to endothelial dysfunction [176] reported in numerous human and animal studies. In turn, this dysfunction promotes a pro-inflammatory environment as evidenced by increased endothelial expression of adhesion molecules, the imbalance of arachidonic acid metabolites, and chemoattractant molecules [176]. Forming a positive feedback loop, vascular inflammation leads to endothelial dysfunction (176). Lipopolysaccharide (LPS) from the bacterial cell wall [177] and C-reactive protein [178] are strong triggers for inflammation and endothelial vascular dysfunction in humans, as observed in T2D [179,180].
These disorders enable endothelial dysfunction as an early step in pathologies such as atherosclerosis and heart failure [181][182][183][184][185][186] and aging [187], as well as metabolic syndrome [188,189] and diabetes [190,191]. Endothelial dysfunction has been associated in several regions of the vasculature in animals and humans with T2D due to defects in NO-derived vasodilation [192,193], associated with diabetic complications such as nephropathy [194], retinopathy [195], and erectile function in animal models or human [190,196], and associated with cardiovascular and all-cause mortality in diabetic patients [191]. However, vascular complications may also be related to defects in endothelium-derived hyperpolarizing factor (EDHF) [193], which is thought to be an extremely important vasodilator substance, notably in resistance vasculature [64]. Unfortunately, the nature and, indeed, the very existence of EDHF remain obscure. Potentially, there are multiple EDHFs demonstrating vessel selectivity in their actions [197].
Mechanisms are complex and multiple, and etiologies are still at the heart of current research; however, oxidative stress are the common denominator [198] (Figure 6).

Free radicals, NO and NO Synthases
Free radicals are able to modify relaxation or contraction balance in favor of contracting factor release, playing a primordial role in vascular pathologies [198]. O2 .− decreases NO bioavailability, forms peroxinitrites [199,200], and inhibits activity and expression of soluble guanylate cyclase (sGC) [201][202][203]. Peroxinitrites themselves at a high concentration inhibits sGC, prostacyclin production through the nitration of the prostacyclin synthase, inhibits SOD [202], notably in diabetes [204], and uncouples NO synthase, leading to O2 − synthesis. Peroxinitrite has a toxic effect on vasculature and contributes to the disease progression and myocardial damage [205]. This loss of NO availability induces disorders [57] such as the formation of a thrombogenic surface in the vessels, an increase in endothelium permeability and an accumulation of oxy-LDL, an attraction of monocytes and T lymphocytes, smooth muscle cell proliferation, and vascular wall growing, leading to vasculopathies. Deficiency of vascular NO is also associated with altered vasorelaxation in arterial pressure [206,207], atherosclerosis [208], hypercholesterolemia [209,210], vascular aging [62,[211][212][213], metabolic syndrome [189], and diabetes [214,215]. Moreover, this blunted-NO availability is believed to be the primary defect that links insulin resistance and endothelial dysfunction [171], and is associated with oxidative stress, for example, in mesenteric arteries from established T2 models Otsuka Long-Evans Tokushima fatty (OLETF) rats [216].
In diabetes, the underlying mechanisms seem to be diverse, but include the effects of hyperglycemia [217], AGEs [211,214,218], uric acid [219], and oxidative stress [213] (Figure 6), and polymorphisms in eNOS lead to NO deficiency [220]. In fact, a high level of glucose induces an

Free radicals, NO and NO Synthases
Free radicals are able to modify relaxation or contraction balance in favor of contracting factor release, playing a primordial role in vascular pathologies [198]. O 2 .´d ecreases NO bioavailability, forms peroxinitrites [199,200], and inhibits activity and expression of soluble guanylate cyclase (sGC) [201][202][203]. Peroxinitrites themselves at a high concentration inhibits sGC, prostacyclin production through the nitration of the prostacyclin synthase, inhibits SOD [202], notably in diabetes [204], and uncouples NO synthase, leading to O 2´s ynthesis. Peroxinitrite has a toxic effect on vasculature and contributes to the disease progression and myocardial damage [205]. This loss of NO availability induces disorders [57] such as the formation of a thrombogenic surface in the vessels, an increase in endothelium permeability and an accumulation of oxy-LDL, an attraction of monocytes and T lymphocytes, smooth muscle cell proliferation, and vascular wall growing, leading to vasculopathies. Deficiency of vascular NO is also associated with altered vasorelaxation in arterial pressure [206,207], atherosclerosis [208], hypercholesterolemia [209,210], vascular aging [62,[211][212][213], metabolic syndrome [189], and diabetes [214,215]. Moreover, this blunted-NO availability is believed to be the primary defect that links insulin resistance and endothelial dysfunction [171], and is associated with oxidative stress, for example, in mesenteric arteries from established T2 models Otsuka Long-Evans Tokushima fatty (OLETF) rats [216].
In diabetes, the underlying mechanisms seem to be diverse, but include the effects of hyperglycemia [217], AGEs [211,214,218], uric acid [219], and oxidative stress [213] (Figure 6), and polymorphisms in eNOS lead to NO deficiency [220]. In fact, a high level of glucose induces an uncoupling of eNOS [221], and, although translocation to the membrane operates, this might be an inactivated form of the enzyme [222]. eNOS is not the only form to play a role in diabetes and its complications. In fact, NOS-opathies include three isoforms: neuronal (nNOS; NOS1), inducible (iNOS; NOS2), and the most well studied endothelial (eNOS; NOS3). Deletion of all three in mice results in spontaneous coronary artery diseases, myocardial infarction, and sudden cardiac death, [223,224] and results confirmed a protective role of eNOS and nNOS, whereas iNOS was found to exert an unfavorable role. Khanna et al. recently reviewed the implication of isoforms in diabetic cardiomyopathy and highlighted the important role of epigenetic modifications in the regulation of gene expression [225]. nNOS, originally expressed throughout the central and peripheral nervous system, is sympathoinhibitory in a range of diseases including chronic heart failure, chronic renal failure, and hypertension [226]. Moreover, nNOS, expressed also in macula densa cells and pylor, is involved in the pathogenesis of renal hemodynamic changes [227] and gastropyloric dysfunction [228] associated with diabetes. However, a characteristic feature of iNOS is its lack of expression in strictly resting cells. Instead, it is induced by immunological stimuli, which led to its original designation as inducible NO synthase [229]. The host cell localization of iNOS has been mainly investigated in macrophages, neutrophils, and smooth muscle cells, where the production of NO is more robust (µm vs. nM for eNOS and nNOS), continually (some days vs. min.) The authors of [230] initially intended to compensate the downregulation of eNOS by oxidative stress [231]. However, like a double-edged sword, the inflammatory cytokines, importantly, TNFα and C-reactive protein at the same time, will activate NADPH oxidase, which in turn produces O 2 .´. Excessive NO concentration produced reacts with O 2 .´f orming peroxynitrite and contributes to an uncoupled iNOS due to the substrate limitation, and therefore the production of ROS [232]. Therefore, the link of oxidative stress and inflammatory response leads to decreased NO bioavailability causing endothelial dysfunction and contractile dysfunction [233], as shown in diabetic complications [234][235][236].

Iron and Non-Transferrin-Bound Iron (NTBI)
Sometimes, the complex interactions between iron, oxidative stress, inflammation, and diabetic complications [247] have attracted considerable interest despite a poor understanding of the mechanisms involved. Numerous forms of body iron exist, and only forms not bound to transferrin or other iron-binding proteins named non-transferrin-bound iron (NTBI) seem to be implicated in oxidative damages due to their high reactivity [248]. NBTI could be considered a biomarker of the side effect of iron in diseases, greatly correlated with Hb1Ac [249]. Recently, Aljwaid et al. [249] confirmed association of NTBI with the risk of vascular complications in diabetes already highlighted 10 years earlier [250][251][252], because NBTI is easily accessible to plaque as well as endothelial cells, macrophages, and smooth muscle cells. Inflammation contributes to iron-mediated endothelial dysfunction, characterized by a high release of iron by infiltrated macrophages, an increase in E-selectin, and other adhesion molecules implicated in atherosclerotic plaque [247,253]. Iron can enter into the atherosclerotic lesion in the form of free hemoglobin, which is prone to oxidation, and can form methemoglobin, ferryhemoglobin, and release heme. All of these exert pro-oxidant and pro-inflammatory effects on the vascular wall [253]. Vinchi et al. [253] summarized current knowledge about the role of hemoglobin, heme, and iron through controversial epidemiological studies and concluded, given more evidence, their negative impact, compared with the innocent role of iron in atherosclerosis. The chronic increase in the release of hemoglobin and heme (hemolysis) is associated with endothelial dysfunction and reduced NO bioavailability [254] and with coagulopathy [255,256] and vasculopathy [256], as observed in diabetes [257], greatly reviewed by Vinchi et al. [258].

Nutritional Prevention: Antioxidants against Diabesity and Complications
Regarding the low level of antioxidant enzymes expression in the pancreas [80], combinations of conventional antidiabetic treatments with antioxidants were quickly privileged [259]. A Mediterranean diet (MedD) is characterized by abundant plant foods (fresh fruit, vegetables, breads, other forms of cereals, seeds, etc.), olive oil as the principal source of fat, and wine. The PREDIMED study examined the effect of a one-year MedD on oxidative and inflammatory parameters in subjects with a high risk for cardiovascular diseases. Results showing that the MedD increases plasma non-enzymatic antioxidant capacity, decrease the biomarkers of atherosclerosis,have anti-inflammatory effect in addition to the improvement of lipid profile, insulin sensitivity, blood pressure, and carotid atherosclerosis. Adherence to MedD reduces the incidence of T2D, metabolic syndrome, and diabetic retinopathy. However, the MedD have no effect on diabetic neuropathy, highlighting complexity to recommend an ideal model for diabetic complication prevention. In patients with newly diagnosed T2D, consumption of this diet resulted in a greater reduction of HbA1c levels, a higher rate of diabetes remission, and delayed need for diabetes medication [260]. Moreover, a Mediterranean diet enriched with extra-virgin olive oil but without energy restrictions reduced diabetes risk among persons with a high cardiovascular risk [261]. Antioxidants act synergistically or by trapping single electrons to free radicals or by reducing ROS enzymatically. Some antioxidants such as vitamins E (tocopherol), C (ascorbate), and Q (ubiquinone), and carotenoids or polyphenols come from food. Inhibition of hyperglycemia-induced ROS production using transgenic antioxidant enzyme expression or antioxidant compounds prevents the development of experimental diabetic retinopathy [262], nephropathy [263,264], neuropathy [265], and cardiomyopathy [266]. Additionally, the mechanisms behind the anti-inflammatory effect of carotenoids (β-carotene and lycopene) have been recently described: both decrease TNFα-mediated ROS generation and increase NO bioavailability at the endothelial level, linking oxidative stress inflammation and vascular beneficial impact [267]. In humans, some large epidemiological studies such as the Linxian study, the Clark study, the Qixia study, the NPC study, or the SU.VI.MAX study in France, the feasibility and efficacy to prevent cancer or mortality with moderate doses of antioxidants has been demonstrated in healthy subjects. Zatalia et al. [16] recently listed all the beneficial effects observed in animals and humans, from vitamins and supplements, plants but also drugs used for treating diabetes and its complications. These experimental and human studies led to a proposal for nutritional prevention to inhibit diabetic complications. Table 1 resumes some classical products that have potential cardiovascular protective effects. We will now see different management strategies of diabetes and complications using non-exhaustive examples of the interest inspired by plants, fruits and vegetables, polyphenolic compounds, and even some drugs used today in the treatment of diabetes with an antioxidant activity (Tables 2-7).

Plant Therapy
Plants have been used from a long time by Chinese, African, and South American peoples as traditional medicines and is used by about 60% of the world's population. The first texts written about herbal medicine are etched in clay. It includes a series of tablets engraved in cuneiform, and its authors, the Sumerians, drafted them 3000 years before the common era. They used plants such as myrtle, hemp, thyme, and willow. From century to century, Theophrastus, Aristotle, Pliny the Elder, and Dioscorides deepened their knowledge of plants and their properties. Morphine, aspirin, quinine: What do they have in common? All come from nature and have led to major drugs. Morphine is extracted from opium (Papaver somniferum), aspirin is extracted from willow bark, and quinine is from a tree from the Cordilleras in the Andes called the cinchona. The world contains many molecules with interesting biological properties, but they must be highlighted. Recently, there has been considerable interest in finding natural antioxidants from plant materials to replace synthetic ones, and natural antioxidants occur in all higher plants and in all parts of the plant (wood, bark, stems, pods, leaves, fruit, roots, flowers, pollen, and seeds) [269]. There have been many investigations into the effects of these plants and their antioxidant ingredients on diabetes and its complications, and good results have been achieved. Dixit et al. focuses on Indian Herbal drugs and plants used in the treatment of diabetes, especially in India [270]. Dodda and Ciddi [15] reported on other plants used in the management of diabetic complications (nephropathy, neuropathy, cataract, and retinopathy) and, last year, Qiang et al. [271] demonstrated the protective effect of Sancaijiangtang on NO and ET-1 dysfunction observed in the vessels of T2D patients. Table 2 shows antioxidant properties of some of these plants, except from those treated by Dixit in his review.
If herbal medicine enjoys an extraordinary craze across the world, this is not just a matter of fashion. Of course, our era is deeply marked by the search for a healthier life, a return to nature and essential values. One recent example is the use of Stevia, with 200 species around the world growing primarily in the Amambay mountain range of Paraguay [272]. Stevia rebaudiana, the only species with the ability to sweeten with no caloric value, contain specific substances (glycosides) in leaves that are rich in vitamins and complements [273]. Research on diabetic rats has shown the antihyperglycemic, insulinotropic, and glucagonostatic actions of stevia [274] and its ability to reduce postprandial blood glucose levels in type 2 diabetic patients, indicating its beneficial effects on glucose metabolism [275]. Stevia offers an ideal alternative to sugar, well tolerated, with a zero glycemic index and no pharmacological effect in T1D and T2D patients [276].

Fruits and Vegetables
Scientific and medical interest in cardiovascular health benefits of fruit-and vegetable-rich diets has grown exponentially in recent years, due to compelling epidemiological evidence showing that the consumption of fruits and vegetables might reduce the risk of cardiovascular diseases [10][11][12][13][14]. Although studies demonstrate no significant beneficial effect against diabetes [293], others highlight a decrease in the risk to develop diabetes [294,295], which was confirmed by a recent meta-analysis on diets rich in green leafy vegetables [296]. Their antioxidant capacities in humans have also been demonstrated in many studies, namely, the effects of strawberries and tomato juice on metabolic syndrome, hyperlipidemia, and T2D [297][298][299]. Table 3 shows experimental studies that evaluate the effect of natural antioxidant products, fruits, and vegetables on diabetes and its related complications.  Recently, studies suggested that these beneficial effects could be due to nitrate content [318][319][320]. Machha and Schechter [321,322] reviewed and reported the beneficial effects of nitrite and nitrate on cardiovascular health, especially with respect to vascular function. Nitrites and nitrates, the content of the fruits and vegetables [323] and direct eNOS subtracts, can improve NO bioavailability in the vasculature and improve endothelial function and all the beneficial effects of NO, nitrites and nitrates as a substrate to eNOS. This evidence has been shown by several in vitro and in vivo animal models [324][325][326] and in humans [325,327,328] to increase the bioavailability of NO to reduce vascular tone, blood pressure, and micro-and macrovascular complications, and improving insulin sensitivity is certainly an attractive therapeutic target in T2D.
Even though antioxidant and anti-inflammatory mechanisms by which fruits and vegetables exert their protective effects are not entirely clear, some studies have identified several bioactive components such as carotenoids, vitamins, fiber, magnesium, and potassium as acting synergistically or antagonistically to promote a holistic beneficial effect. For example, vitamin C restores endothelial function in T1D patients, leading to decreased micro-and macrovascular complications [329]. Chronic vitamin E, with low (100 UI/d, 3 months) or high (250UI/d, 6 months) doses, decrease lipid peroxidation in T1D patients [330,331]. Vitamin E is the best example that shows the complexity of antioxidant studies. In fact, this antioxidant supplement has been investigated extensively. Since 1998, Heinonen et al. [332] has suspected an increase in prostate cancer, not confirmed later by Lippma et al. [333] and Gaziano et al. [334] in 2009. However, in 2005, Miller et al. [335] described an increase in all-cause mortality, and the SELECT study was stopped in 2008 due to an increase in prostate cancer with 400UI/d of vitamin E [336]. Moreover, a randomized clinical trial with vitamin E showed no cardiovascular benefits, mainly in non-diabetic subjects [337]; this was confirmed later by a HOPE clinical trial [338,339]. However, an analysis of all data in a sub-group of subjects with diabetes and haptoglobin 2-2 genotype in HOPE and ICARE studies revealed that, in fact, vitamin E (400UI/d, 18 months) reduced the rate of cardiovascular events in these high risk subjects [340,341], which was confirmed in a recent meta-analysis [342]. Table 4 shows antioxidant efficacy of vitamins and supplements focus in diabetes and its complications.

Polyphenols: Extract Versus Molecular Compound
Polyphenols are a large and heterogeneous group of phytochemicals of plant-based foods, including tea, coffee, wine, cereal grains, vegetables, legumes, fruits, and berries [372]. And the largest and best-studied polyphenols are flavonoids, which include several thousand compounds, among them flavonols, flavones, flavonones, flavan-3-ols, anthocyanins, and isoflavones [373]. The estimated intake of dietary polyphenols is approximately 1 g/day [374]. Increasingly, the dietary recommendations for individuals at risk of T2D emphasis the intake of plant food products, such as whole grains, berries, fruits, and vegetables, all known to be excellent sources of dietary fiber, but also good sources of variable polyphenolic compounds. In fact, epidemiological studies report an inverse association between dietary polyphenol consumption and both diabetes [17][18][19][20] and more generally in chronic diseases such as cardiovascular diseases, atherosclerosis, hypertension, and cancer [375].
As shown before, vascular protection may also be due to the direct action of polyphenols on the endothelial function. In fact, polyphenols are able to stimulate the endothelial formation of NO and EDHF in isolated blood vessels, and improve endothelial function in humans. Schini-Kerth et al. [21] described the vascular protection led by natural product-derived polyphenols in ex vivo and experimental models of cardiovascular disease, including metabolic syndrome and diabetes. Recently, Franzini et al. [376] indicated that diets that contain a high level of polyphenol-rich natural sources such as red wine, grapefruit, berries, and dark chocolate, improved endothelial function in a low cardiovascular risk population, and Khan et al. [377] discusses the effects of cocoa polyphenols on cardiovascular-related inflammation. Table 5 shows the effect of polyphenol-rich natural sources on human vascular function. Table 5. Beneficial effects of several polyphenol-rich natural sources on vessels in humans.

Natural Sources Human Studies Efficacy
Hypertensive patients [402] no effect on blood pressure Pomegranate juice Severe carotid artery stenosis [403] Hypertensive patients [404] Ó blood pressure, Óartery thickness Ó blood pressure Strawberry Obese patients [405] Ó risk factors for CVD and stroke
Besides their beneficial effects on endothelial function and vascular homeostasis, they also influence glucose metabolism by several mechanisms, such as the inhibition of carbohydrate digestion and glucose absorption in the intestine, the stimulation of insulin secretion from the pancreatic β-cells, the modulation of glucose release from liver, the activation of insulin receptors and fatty acid) T2D patients [409] Improve endothelial function Ò HDL CV: cardiovascular; FMD: flow-mediated dilatation (technic to measure endothelial function in humans).
Besides their beneficial effects on endothelial function and vascular homeostasis, they also influence glucose metabolism by several mechanisms, such as the inhibition of carbohydrate digestion and glucose absorption in the intestine, the stimulation of insulin secretion from the pancreatic β-cells, the modulation of glucose release from liver, the activation of insulin receptors and glucose uptake in the insulin-sensitive tissues, and the modulation of hepatic glucose output [410]. Many polyphenols have been shown to inhibit mostly α-glucosidase activity in vitro (anthocyanins, catechins, flavanones, flavones, flavanols, isoflavones, phenolic acids, and proanthocyanidins), whereas α-amylase activity is inhibited only by phenolic acids and some flavonols such as quercetin, luteolin, and myricetin. As regards the various effects of polyphenols, very few of them are able to induce insulin secretion from cultured cells or islets isolated from pancreas (cyanidin and delphinidin, epicatechin and EGCG, rutin, quercetin, apigenin, etc.) and inhibit the sodium-dependent glucose transporter (SGLT1) and the glucose transporter GLUT2) (tea catechins and quercetins) [410]. Recently, Hanhineva et al. [410] listed the impacts of dietary polyphenols on glucose metabolism with in vitro and in vivo studies and highlight the protective role of dietary rich in polyphenols on carbohydrate metabolism in both animals and humans. For example, Rostami et al. [411] demonstrated that cocoa is effective in improving TG levels, decreasing blood pressure, and fasting blood sugar in T2D patients with hypertensive complications. A meta-analysis of eleven randomized controlled clinical trials showed that resveratrol significantly improves glucoregulation and insulin sensitivity in diabetic patients, but not control participants [412]. Similar results were obtained in a second meta-analysis that included only T2D patients [413]. One recent review [414] reported the latest advances regarding the timing, dosage, formulation, bioavailability, toxicity of resveratrol in human, focusing on cancer, neurogeneration and diabetes, obesity, and cardiovascular diseases. Curcumin has been reported as a potent scavenger of a variety of ROS [415], exhibiting anti-inflammatory activity as well as antioxidant properties [416]. The phenolic (OH) structure of curcumin was believed to be essential for curcumin's anti-oxidant activity [417]. Novelle et al. [414] concluded about difficulties of establishing a specific range of safety/efficacy for particular doses of resveratrol for particular populations, and many discrepancies and conflicting information must be resolved before recommending the use of resveratrol. Tables 6  and 7 show the effect of polyphenol-rich natural sources on human prevention of T2D on in vitro and in vivo models of diabetes and complications, respectively. Table 6.
Beneficial effects of several polyphenol-rich natural sources on Human cardio-metabolic diseases.

Single compounds
Quercetin Myricetin different national public health registers [418] Ó risk T2D an chronic disease The Woman's Health Study [419] no effect EGCG extract Overweight or obese men [420] no effect on insulin sensitivity, no effect on glucose tolerance, modest Ó in DBP T2D patients [421] no effect on insulin sensitivity, T2D patients [408,422] no effect on HbA1c and glycaemia and Insulin resistance Lipoic acid T2D patients [423] Ò insulin sensitivity obesity, and cardiovascular diseases. Curcumin has been reported as a potent scavenger of a variety of ROS [415], exhibiting anti-inflammatory activity as well as antioxidant properties [416]. The phenolic (OH) structure of curcumin was believed to be essential for curcumin's anti-oxidant activity [417]. Novelle et al. [414] concluded about difficulties of establishing a specific range of safety/efficacy for particular doses of resveratrol for particular populations, and many discrepancies and conflicting information must be resolved before recommending the use of resveratrol. Tables 6 and 7 show the effect of polyphenol-rich natural sources on human prevention of T2D on in vitro and in vivo models of diabetes and complications, respectively. Overweight or obese men [420] no effect on insulin sensitivity, no effect on glucose tolerance, modest ↓ in DBP T2D patients [421] no effect on insulin sensitivity, T2D patients [408,422] no effect on HbA1c and glycaemia and Insulin resistance Lipoic acid T2D patients [423] ↑ insulin sensitivity Ѡ-3

Whole polyphenols diets/foods
Apple Middle-age women [419] Men and women [418] Ó risk T2D Ó risk T2D Cocoa drink Hypertensive patients [402] no effect on insulin resistance no effect on blood pressure

Krill oil (rich in
Single compounds Quercetin Myricetin different national public health registers [418] ↓ risk T2D an chronic disease Quercetin Kaemferol Myricetin Apigenin Luteolin The Woman's Health Study [419] no effect EGCG extract Overweight or obese men [420] no effect on insulin sensitivity, no effect on glucose tolerance, modest ↓ in DBP T2D patients [421] no effect on insulin sensitivity, T2D patients [408,422] no effect on HbA1c and glycaemia and Insulin resistance Lipoic acid T2D patients [423] ↑ insulin sensitivity Ѡ-3

Current Medications
Some modern drugs are derived from traditional medicine: anti-malarials (artemisinin, quinine), anti-asthmatics (cromolyn), anti-cancer (etoposide, vinca alkaloids), anti-coagulants (huridine), anticholestérolémiants (Lavastatine), and analgesics (opiates) [454]. Moreover, drugs used to treat diabetes have an antioxidant activity [16]: a scavenger of ROS and a modulator of antioxidant enzymes activities by several mechanisms. Some of them have beneficial effects on diabetes complications such as nephropathy-angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and melatonin, and neuropathy and retinopathy-melatonin and α-lipoic acid. Many of them have beneficial effects against cardiovascular diseases: caffeic acid, phenethyl ester, carvedilol, and metformin [16]. In fact, metformin, the currently used biguanide antihyperglycemic agent, can decrease xanthine oxidase activity and TNFα production, chelates metal ions, and inhibits AGE formation [455] with an intracellular modulation of free radical production [72].

Discussion and General Conclusion
In the last few years, there has been an exponential growth in the field of herbal medicine, and these drugs are gaining popularity. Many traditional medicines in use are derived from medicinal plants, minerals, and organic matter, and many conventional drugs have been derived from prototypic molecules. The use of medicinal plants for therapeutic purposes is a practice as old as human history. Some studies and population observations highlight a real effect of plants on health and management of diabetes complications. Today, the WHO has listed 21,000 plants, which are used for medicinal purposes around the world, but the expert committee on diabetes has recommended that traditional medicinal herbs be further investigated.
Nutrition and diet quality are key elements in the acquisition, control, and potential treatment of many chronic diseases and adverse health conditions. Higher consumption of fruits and vegetables has been associated with a lower risk of several diseases, including cardiovascular disease [11,12]. Increased physical activity and dietary management implemented by health-care professionals is fundamental to initial treatment of T2D and has been recommended for a long time by international consensus [456]. Meta-analyses of exercise and diet studies have concluded that concentrations of HbA1c can be lowered by aerobic and resistance exercise and by dietary intervention [457,458], more precisely, intensified, targeted, multifactorial interventions compared to conventional intervention [459]. However, few studies have determined whether treatments affect endothelial dysfunction and oxidative stress. If multifactorial treatment does have an effect, then markers of endothelial dysfunction and oxidative stress would be expected to be less associated with cardiovascular death and all-cause mortality in these patients. In fact, most of the studies have reported the beneficial effects of natural products-rich in antioxidant activities, leading to protect vessels against oxidative stress, loss of vascular homeostasis, and diabetic complications. Recent data have supported that the hyperglycemic environment may be remembered in the vasculature, a metabolic or "hyperglycemic memory" explaining the progression of diabetic vascular complications despite normoglycemia restoration [460]. Moreover, endothelial progenitor cells as a biological marker of peripheral artery disease [390] have highlighted a real interest in protecting the vascular arch [461]. Thus, taking all of this literature together, blood vessels could be a good marker and strategy to monitor complications, especially in diabetes.
Observational cohort studies support that consumption of sugar-sweetened beverages, including artificially beverages and fruit juice, are associated with incident T2D, independently of obesity. Both were unlikely to be healthy alternatives to sugar-sweetened beverages for the prevention of type 2 diabetes, and, under assumption of causality, there consumptions may be related to a substantial number of cases of new onset diabetes [462]. The local food environment may influence individual (including food choices) and community health [463]. Today, the objective is to promote the consumption of non-industrial and natural products instead of concentrated fruit juice intake. In fact, the association between fruits and vegetables consumption and weight development has been summarized in the ISA-FRUIT Project of the EU from 2008, and 7/16 studies [464] and several prospective cohort studies [296,465] and the EPIC-Norfolk Study [466] have highlighted an inverse association between "unworked" fruits and vegetables consumption and health outcomes including obesity, cardiovascular, and diabetes. However, others studies have not demonstrated the effectiveness of fruits and vegetables to have health effects or to prevent chronic diseases. These results suggest that there are sub-types within larger categories of food environments that are differentially associated with adverse health outcomes [467]. Differences in the nutrient contents by group could explain differences and raise difficulties of interpreting the results of different human studies. There is a need to conduct clinical research, developing simple bioassays for biological standardization, pharmacological, and toxicological evaluation, to study the effects of natural food on health.
It would actually be profitable to propose tables' effects of antioxidants, with corresponding doses and diseases treated; still, however, the study of antioxidants is very difficult and complex. Many parameters can influence the results of clinical studies: a different design in terms of types and origins of antioxidants, doses, formulation, absorption, biodisponibility, and times of treatments; the studied population, genotype sub-type of patients, types of medication, and progression of the disease, with a time course of diabetes and complications; and the methods of assessment and their limitations [468][469][470]. The international society of antioxidants in nutrition and health (ISANH) work today to propose guidelines with all these objectives. Although the results of clinical studies about the therapeutic use of antioxidants are quite controversial, all data reported in this review and in others provide real hope for their use, especially in the prevention of diabetic complications. Food is the first pillar of patient care before the introduction of medications. Wealth, nutritious additions, and a contribution of bioactive molecules (vitamins, polyphenols, etc.) with antioxidant properties is actually a real asset in the prevention of chronic diseases, while the importance of prevention should not be underestimated. All publications by Dal et al. demonstrated the interest of the use of natural antioxidants (red wine polyphenols) to prevent and treat diseases with endothelial dysfunction related to oxidative stress [62,64,213,471,472]. Moreover, our recent works carried out on in vitro and in vivo models of metabolic disorders have allowed us not only to involve oxidative stress in the pathophysiology of disorders but also to demonstrate that natural antioxidant compounds help to prevent or reduce complications (polyphenols from green tea and red wine [442,473], red cabbage, Dal S, under publication). One study in process in the lab focusing on antioxidants in T1D seems be a new target for the diabetic optimization of management [474].
All of our studies, and studies mentioned in this review, demonstrate the ability of antioxidants to prevent or counteract excessive ROS production by increasing endogenous antioxidant defenses. We think now that a new strategy might be to prevent the overproduction of ROS instead of only scavenging the already formed ones, because of the "cardio-metabolic memory." Today, an optimal understanding of the beneficial mechanisms of functional products or functional foods [475] will not allow for more personalized care, depending on the status of cardiovascular and metabolic patients.
Author Contributions: SD and SS design the paper, SS wrote part 2 and reviewed it, and SD wrote the other parts and reviewed the paper.