Polyphenols mediated attenuation of diabetes associated cardiovascular complications: A comprehensive review

Abstract

Background

Diabetes mellitus is a common chronic metabolic disorder that is characterized by increased levels of glucose for prolonged periods of time. Incessant hyperglycemia leads to diabetic complications such as retinopathy, nephropathy, and neuropathy, and cardiovascular complications such as ischemic heart disease, peripheral vascular disease, diabetic cardiomyopathy, stroke, etc. There are many studies that suggest that various polyphenols affect glucose homeostasis and can help to attenuate the complications associated with diabetes.

Objective

This review focuses on the possible role of various dietary polyphenols in palliating diabetes-induced cardiovascular complications. This review also aims to give an overview of the interrelationship among ROS production (due to diabetes), inflammation, glycoxidative stress, and cardiovascular complications as well as the anti-hyperglycemic effects of dietary polyphenols.

Methods

Various scientific databases including Scopus, Web of Science, Google Scholar, PubMed, Science Direct, Springer Link, and Wiley Online Library were used for searching articles that complied with the inclusion and exclusion criteria.

Results

This review lists several polyphenols based on various pre-clinical and clinical studies that have anti-hyperglycemic potential as well as a protective function against cardiovascular complications.

Conclusion

Several pre-clinical and clinical studies suggest that various dietary polyphenols can be a promising intervention for the attenuation of diabetes-associated cardiovascular complications.

Introduction

Diabetes mellitus (DM) is a chronic metabolic complication characterized by persistent hyperglycemia and imbalance in carbohydrates, fats, and protein metabolism due to impaired insulin production, action, or both. There are three types of diabetes mellitus which include Insulin-dependent diabetes mellitus T1DM (no insulin production), Insulin-independent diabetes mellitus or T2DM (impaired insulin sensitivity or production), and Gestational diabetes (develops during pregnancy) [1–3].

Among the three DMs, T2D is one of the rapidly growing metabolic disorders which is estimated to affect 693 million adults by 2045 [4]. According to estimates, among people ages 20 to 99, diabetes accounts for up to 10% of all-cause deaths worldwide [5]. Over the past few years, diabetes and pre-diabetic conditions have become more common in India. According to the International Diabetes Federation, 77 million Indians were predicted to have diabetes in 2019 with an estimated prevalence of 8.9% among adults. India has overtaken the United States as the nation with the second-largest diabetes population [5].

Compelling evidence from the research done globally suggests that high glucose levels may be a contributing factor to cardiovascular diseases (CVD). For example, activation of the advanced glycated end-product (AGE) receptor may accelerate the development of atherosclerotic plaque by increasing intima-medial thickness and arterial stiffness [6]. Further, hyperglycemia stimulates the differentiation of monocytes into macrophages, which results in the formation of foam cells and intracellular accumulation of oxidized lipids [7]. Also, fluctuations in blood sugar levels may encourage oxidative stress and protein kinase C activation, which can result in fibrosis and endothelial dysfunction [8]. Various researchers have demonstrated a strong correlation between insulin resistance (IR) and the onset and progression of coronary atherosclerosis which can lead to an elevated risk of adverse cardiovascular (CV) outcomes [9–11].

Globally, a variety of medications are used to control diabetes which includes SLGT2 inhibitors, thiazolidinediones, sulfonylureas, biguanides, meglitinides, α-glucosidase inhibitors, GLP-1 analogs and DPP-IV inhibitors [12, 13]. These anti-diabetic medications available in the market come with a number of adverse effects such as weight gain, liver damage, gastrointestinal discomforts, etc. [14–19] (Figure 1). Therefore, extensive research is being done to develop hypoglycemic medications that are both safe and affordable. Since the dawn of time, different phytoconstituents have been employed to cure a variety of illnesses. Traditional medical practices based on plant extracts have shown to be more accessible, therapeutically successful, and generally less harmful than contemporary pharmaceuticals [20]. Polyphenols are the secondary metabolites found in plants and are currently being researched for their potential health advantages. These compounds exhibit remarkable antioxidant and anti-inflammatory properties due to the presence of hydroxyl groups in their phenolic structure [21]. The antioxidant properties of polyphenols help them prevent the oxidation of biomolecules by readily donating protons or electrons to neutralize free radicals or react with them to produce stable compounds [21, 22]. Some of the possible mechanisms of polyphenols' antioxidant action include the direct scavenging of reactive free radicals, the chelation of trace metal ions involved in free radical formation, the inhibition of free radical-producing enzymes, and the regeneration of membrane-bound antioxidants like α-tocopherol [22]. Various studies showed clearly that the main components of green tea polyphenols such as epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), epigallocatechin gallate (EGCG), and gallic acid (GA), efficiently lowered the α-tocopheroxyl radical and regenerate α-tocopherol [23]. Polyphenols exhibit anti-diabetic effects via increasing intestinal L-cell secretion of glucagon-like peptide-1 (GLP1), inhibiting dipeptidyl peptidase-4 (DPP4), which lengthens GLP1 half-life, increasing insulin secretion by (direct or indirect) β-cell stimulation, and increased insulin sensitivity on peripheral tissues [24]. Berry polyphenols exhibit anti-diabetic effects via (i) boosting insulin production, lowering apoptosis, and encouraging pancreatic beta-cell proliferation, (ii) controlling the metabolism of glucose by inhibiting absorption or enhancing peripheral tissue glucose uptake through insulin receptor-dependent or independent processes by modifying oxidative stress, inflammation, or the cell's perception of its energy status [25]. According to studies, catechins lower levels of fatty acids, triacylglycerol, and cholesterol by inhibiting gene expression, while increasing the expression of the GLUT1 and GLUT4 transporters, which consequently normalizes blood sugar levels. [21] Hesperidin alters the function of GLUT2 to decrease intestinal glucose absorption and control the postprandial glycemic response to orange juice [26] Apigenin exhibits inhibition of GLUT2, GLUT5, and GLUT7 i.e. it can prevent small intestine epithelial cells from absorbing glucose [27]. EGCG, stilbene, and resveratrol aid in the translocation of GLUT4 to the plasma membrane, suggesting that they encourage tissue cells to take up glucose to lower hyperglycemia [28]. Thus, preclinical research has provided indisputable proof that polyphenols have both antioxidant and anti-diabetic activities [21, 22]. The aim of this review is to provide an overview of the modulatory role that various dietary polyphenols have in lowering diabetes-associated cardiovascular complications.

Fig. 1.

Different classes of anti-diabetic drugs and their mode of action

Materials and methods

The survey of the literature of this review was acquired by probing various scientific databases including Scopus, Web of Science, Google Scholar, PubMed, Science Direct, Springer Link, and Wiley Online Library with no restriction in terms of date, language, and search filters. The following keywords were used as the search criteria. Keywords: “Diabetes”, “diabetes mellitus", "diabetic", "type 2 diabetes", "type 2 diabetes mellitus", “cardiovascular complications”, “hyperglycemia”, “polyphenols”, “postprandial”, “insulin-resistance”, “oxidative stress”, “glycoxidative stress”, and “carbohydrate metabolism”, “coronary heart disease", “pre-clinical", clinical", "trial” "heart diseases", “atherosclerosis”

Search strategy

All articles that were retrieved were subjected to title and abstract screening; after that, we checked the entire text to see if the publications were eligible, and irrelevant articles were removed. Finally, the whole texts of the selected publications were studied, and studies that satisfied the study's inclusion criteria were included in the current study.

Inclusion and exclusion criteria

To avoid selection bias, inclusion and exclusion criteria were defined before the literature search. In this sense, randomized controlled trials, meta-analyses, systematic reviews, and clinical/pre-clinical in vitro/in vivo trials carried out in animals and humans were included. Studies that met the following criteria were included in this review: 1) Role of oxidative and glycoxidative stress in the progression of cardiovascular complications 2) Role of polyphenols in attenuating the oxidative and glycoxidative stress 3) Sources, bioavailability, and metabolism of polyphenols 4) Cardiovascular protective effects of polyphenols 5) Polyphenols useful in both diabetes and cardiovascular complications. Studies were excluded if the polyphenols were used as combined therapy with other medications. Studies were also excluded if participants had been diagnosed with a chronic illness other than diabetes, cardiovascular complications, duplicate studies, as well as works written in a non-English language, were excluded.

Data extraction

Two reviewers independently examined the titles and abstracts of each paper, clearing those that did not meet the inclusion requirements or exclusion criteria. The remaining full-text papers were reviewed based on the inclusion and exclusion criteria. If there was disagreement between two reviewers, a third reviewer participated in the conversation to reach a consensus.

Any differences of opinion were discussed until they were resolved between the authors.

AB, SA and BS designed the concept of the manuscript. NK wrote the sections on sources, bioavailability, metabolism and antihyperglycemic potential of polyphenols. GB wrote the sections on oxidative stress, inflammation in diabetes and cardiovascular protective effects of polyphenols. SS wrote the sections on the antioxidative properties of polyphenols and designed the figures. SSB revised and completed the final manuscript. All authors read and approved the final manuscript.

Results

Study selection

According to our search strategy, 2086 records utilizing keywords were found in the searched databases. After removing the duplicate records, 1295 records were extracted. After titles and abstracts were scrutinized, 873 articles that did not meet the selection criteria were eliminated. Authors read complete texts of the 422 remaining papers prior to eliminating the remaining 103 studies that dealt with polyphenols, which were used in combination with other drugs. 117 studies that dealt with patients who had been diagnosed with a chronic condition other than diabetes or cardiovascular problems were further removed. Finally, a total of 201 studies were included in writing this comprehensive review (Fig. 2).

Fig. 2.

PRISMA Flow diagram of study selection in review

Role of Glycoxidative stress and inflammation in the development of CVD

Both oxidative stress and inflammation are interconnected through various cellular cascades. Oxidative stress is produced when there is an imbalance between the antioxidants and Reactive oxygen species (ROS)/Reactive Nitrogen Species (RNS). ROS can be free radicals (superoxide) or non-free radicals (H₂O₂). Prolonged hyperglycemia causes oxidative stress which further leads to the manipulation of various pathways, mainly including inflammatory pathways. Glycoxidative stress (GOS) refers to the oxidative stress induced due to elevated levels of glucose in the blood for a prolonged period of time [29]. In hyperglycemic conditions, activated Protein kinase C (PKC) and Advanced glycation end products (AGEs), uncoupled eNOS by post-translational modification of eNOS at ser-1177 results in the production of ROS and reduction of NO in endothelial cells leading to endothelial dysfunction. NO maintains proper functioning as a vasodilator i.e. antioxidant with anti-inflammatory properties [30]. BH4 (tetrahydrobiopterin) is a cofactor used by eNOS to form NO, but its oxidation by ROS produces peroxynitrite and thus induces the uncoupling of eNOS [31]. In the human body, to counter oxidative stress, there are antioxidant enzymes that help in scavenging ROS, like superoxide dismutases (SOD), thioredoxin, glutathione peroxidases (GPx), and catalase. In diabetics, the excessive production of oxidative stress dominates over anti-oxidant enzymes and thus their activities are reduced. ROS production in diabetes through several factors such as auto-oxidation of glucose, non-enzymatic formation of advanced glycation end products (AGE), the polyol pathway, increased level of FAA (free fatty acids), involvement of leptin and oxidation of LDL, leads to consequent damage of cellular machinery and enzymes, cardiovascular complications, organ damage and development of insulin resistance [32] (Fig. 3).

Fig. 3.

Hyperglycemic induction of ROS production via different cellular cascades

The ROS activates the PKC pathway which stimulates NF-κB resulting phosphorylation of IKB which further undergoes ubiquitination and degradation [33]. Activated NF-κB enters the nucleus and causes the formation of foam cells, proliferation, inflammation, cellular senescence, and apoptosis. It also increases the expression of inducible Nitric Oxide synthase which produces an excess of NO which reacts with free radicals to form peroxynitrate. The peroxynitrate then consequently increases the ROS production and permeability of the mitochondrial membrane. ROS also activates transforming growth factor-β (TGF-β), stress-activated protein kinase, etc. which leads to elicit inflammation and myocardial fibrosis in the diabetes-associated cardiovascular system [34].

CVDs are a major reason for deaths worldwide. Hyperglycemia, hypertension, obesity, dyslipidemia, and insulin resistance increase the risk of CVD. Oxidative stress promotes cardiovascular complications like atherosclerosis, myocardial infarction, vascular dysfunction, arterial hypertension, atrial fibrillation, and heart failure [35]. Diabetic patients are having 2-4 times higher risk of CVD than non-diabetic patients [36]. Glucose-generated excessive production of ROS also promotes vasoconstriction, reduces the availability of NO, increases arterial hypertension, and increases arrhythmia. Endothelial dysfunction causes macro-vascular disease and atherosclerosis. Endothelial dysfunction allows infiltration and oxidation of lipids into the vessel wall which promotes pro-inflammatory reactions via cytokine secretion. In pro-inflammatory reactions, there is a recruitment of monocytes and leukocytes, which get differentiated into macrophages. These macrophages then become foam cells, further enhancing the production of cytokines and thus responsible for the contribution of inflammation and formation of atherosclerotic plaque. The atherosclerotic plaque thickens and clogs the lumen of the vessel resulting in obstruction of the vascular flow with the accumulation of collagen. Further, migration and proliferation of smooth muscle cells result in the rupture of plaque [6]. Oxidative stress induced by diabetes causes oxidation of LDL and many ROS-producing enzymes present in the wall of blood vessels, are activated by glyco-oxidative stress (Figure 4).

Fig. 4.

Process of Atherosclerosis

Polyphenols as an alternative remedy for diabetes-induced Cardiovascular complications

Polyphenols are the secondary metabolites present in plants and are readily being explored for their various health benefits. There is incontrovertible evidence from preclinical studies that depict that polyphenols exhibit anti-diabetic potential and possess antioxidant properties. For instance, berberine is a polyphenol found in the roots of various plants, it has properties to lower blood glucose levels [37]. Red grapes, bilberries, chokeberries, cocoa, coffee, and green tea are all rich in polyphenols and show promising effects in regulating blood glucose levels [38]. According to research, it is found that flavanones, dihydroflavonols, and stilbenes may help older people in lowering the chances of developing diabetes. (Predimed study investigators). Research has shown that different polyphenols such as oleuropein, hydroxytyrosol, catechin, chlorogenic acids, hesperidin, nobiletin, and isoflavones have potent radical scavenging and antioxidant properties [39]. Anthocyanidins and flavan-3-ols can significantly reduce the risk of developing T2D while epicatechin has the ability to neutralize ROS species [40, 41]. Therefore, the anti-diabetic potential of polyphenols can be utilized to manage post-prandial hyperglycemia, whereas the antioxidant properties of polyphenols can be employed to neutralize the oxidative stress (a major cause of cardiovascular complications) caused due to diabetes in the body [42–48]. So, this review focuses on the possible role of various dietary polyphenols in palliating diabetes-induced cardiovascular complications.

Polyphenols: sources, bioavailability, and metabolism in the body

Sources of polyphenols

Polyphenols are secondary metabolites produced in plants having polyphenol structures (i.e., several hydroxyl groups on aromatic rings). Polyphenols are classified into different classes on the basis of the number of phenol rings that are present and the structural elements that bind the phenolic rings with one another. The main classes of polyphenols include flavonoids (which include anthocyanins, chalcones, dihydrochalcones, dihydroflavonols, flavanols, flavanones, flavones, flavonols, isoflavonoids), lignans, non-phenolic metabolites, phenolic acids (which include hydroxybenzoic acids, hydroxycinnamic acids, hydroxyphenylpropanoic acids), other polyphenols (which include, alkylphenols, curcuminoids, furanocoumarins, hydroxybenzaldehydes, hydroxybenzoketones, hydroxycinnamaldehydes, hydroxycoumarins, hydroxyphenylpropenes, methoxyphenols, naphtoquinones, phenolic terpenes, tyrosols) [49]. (Figure 5) Several polyphenols are found in the plants that are edible. There are over 400 edible plant species that contain over 500 different polyphenols in low or high amounts. According to the work done by [50], about two-thirds of dietary polyphenol intake comes from flavonoids, and the remaining one-third is from phenolic acids. There are more than 8000 phenolic molecules that have been identified, which contain one aromatic nucleus and one or more than one -OH group [51].

Fig. 5.

Different classes of polyphenols

Bioavailability of polyphenols

Bioavailability may be defined as the fraction or part of a dose that is available at the site of action in the body. There are various factors that account for the low bioavailability of polyphenols such as the degradation of polyphenols with an increase in pH value from the stomach to the small intestine, poor absorption, and metabolism of polyphenols in the small intestines, and release of polyphenols from food matrix. The low pH in the stomach favors the stability of polyphenols that facilitates the transition of polyphenols from the food matrix into the aqueous phase because of reduced ionic interactions [52]. Glucosidase enzymes present in saliva start to metabolize glycosylated phenolic compounds as they enter the mouth. Several polyphenols remain intact while passing through the stomach whereas others hydrolyze to some extent. Various enzymes need to be modified structurally in order to get absorbed in the gastrointestinal tract. Many phenolic compounds get passively diffused or absorbed by various carriers such as P-glycoprotein and cotransporters for SGLT1. For example, the released aglycons are passively diffused into the enterocytes following which they undergo biotransformation in enterocytes and then in hepatocytes. Afterward, the ensuing metabolites are facilitated to different organs and excreted in the urine [53, 54]. Firstly, polyphenols are digested (to some extent) or modified (structurally) to get absorbed easily into the bloodstream through the gut wall. Afterwards, these polyphenol compounds are transported to the liver through portal veins where different biotransformation reactions take place. These reactions occur in two phases: Phase I involves oxidation and reduction of compounds followed by hydrolysis reactions catalyzed by the CYP450 enzymes. While in Phase II, the resulting compounds are transformed into hydrophobic compounds, or their hydrophobicity is increased to facilitate their elimination from the body. In most edible plants, polyphenols occur as glycosides and as complex oligomeric structures that are poorly bioavailable, which inhibits their reach to the systemic tissues in their native form. These polyphenols are further hydrolyzed by the enzymes present in the intestines and the gut microbiota. The ensuing metabolites of phenols are then absorbed, following which they rapidly undergo extensive phase II metabolism by glucuronyl transferases, sulfate transferases, and catechol methyl transferases yielding glucuronide, sulfate, and methyl conjugates that can be seen in the circulatory system and detected in urine up to 3-4 days after intake [50].

Metabolism of polyphenols

Metabolism of phenolic acids occurs in two phases i.e., Phase I and Phase II. Phase I includes hydrolysis in which polyphenol derivatives undergo various reactions that are catalyzed by several hydrolysis enzymes such as carboxylesterases (critical hydrolysis enzymes in mammals) [54]. These reactions reduce the polarity of aglycones produced, which ultimately increases their absorption by the intestinal epithelium. Oxidation is an important process in phase I of biotransformation. The oxidation process is an enzyme-based reaction carried out by CYP450 (microsomal cytochrome). Microbiota present in the colon of humans catabolize polyphenols to a large extent which is followed by absorption [55]. These absorbed polyphenol compounds are then transported to the liver where they are transformed into monosulphates through a conjugation reaction. Afterward, polyphenol metabolites that are not absorbed are expelled through feces from the body. During Phase II, the polarity of metabolites is increased by the addition of chemical radicals to polyphenol metabolites [56]. Some of the enzymes that are involved in the metabolism of polyphenols in Phase II are Uridine-5-diphosphate, glucuronide transferase, and catechol-O-methyltransferase [54]. The polyphenol derivatives such as aglycons or hydroxyphenylacetic acids following the enzymatic processing by bacteria are absorbed by the epithelial cells of the small intestine [57]. Polyphenols undergo several metabolic transformations in phase II and they are characterized by the conjugation, O-methylation, and O-dimethylation of hydroxy groups. Subsequent to these transformations, there is the generation of water-soluble conjugated metabolites (glucuronides and methyl derivatives) which are then released into the systemic circulation and reach the target organs [58] (Figure 6).

Fig. 6.

Metabolism of polyphenols via Phase I and Phase II

Anti-oxidative properties of polyphenols

Polyphenols are well proclaimed for their role as antioxidants, scavenging free radicals (ROS) along with the anti-inflammatory action. Studies have been conducted to note that these polyphenols modify the expression of genes like lipoxygenase (LOX), nitric oxide synthase (NOS), cyclo-oxygenase (COX), and pro-inflammatory cytokines [59]. Due to the presence of polyphenols, aromatic medicinal plants are said to possess remarkable antioxidant properties. The free radicals generated have a very negative outcome of oxidative stress which results in compromising our immune system [60]. The excess of ROS in our body reacts with lipids, DNA, and cellular proteins to cause genomic instabilities, injury to the plasma membrane integrity, and oxidative modifications which may lead to proteolytic degradation of proteins or inactivation of enzymes. The antioxidants are capable of negating the harmful effect of these reactive oxygen species (ROS) [61]. One of the remarkable features of antioxidants is their reducing power i.e., the ability to donate electrons [62]. The antioxidant property of polyphenols is shown to reduce the severity of inflammation by targeting different stages of the inflammatory cascade [63].

A wide variety of compounds with antioxidant activities, such as flavans-3-ol (condensed tannins), gallic acid derivatives (hydrolysable tannins), flavonols, and anthocyanins are present in fruit polyphenols [44]. Certain studies also proved that the antioxidant property of polyphenols has shown to be successful in slowing down the process of aging and age-related diseases [64]. Polyphenols as antioxidants exhibit a negative impact on the hyperactivation of pro-inflammatory cytokines and ROS for the treatment of COVID-19 patients [65]. The antioxidant and antiviral properties of polyphenols could be implemented to inhibit the onset and development of viral diseases [66].

The oxidative stress caused by the hyperglycemia conditions exerts an increase in proinflammatory response by increasing NF-κB gene expression and IL-6 secretion. In addition, it also changed the production of ET-4, eNOS, and NO vasoactive markers. The plant-based polyphenols help to safeguard from oxidative stress caused by hyperglycemia [67].

Anti-hyperglycemic effects of Dietary polyphenols

Carbohydrate metabolism and postprandial hyperglycemia

Carbohydrates are the most abundant biomolecules present on earth. These are mainly categorized into three major classes based on their structures: 1) Simple carbohydrates (monosaccharides and disaccharides), such as glucose or sucrose. 2) Complex sugars, such as glycogen, cellulose, and starch (multiple conjugated molecules of glucose); and 3) Glycoconjugates, which are altered forms of glucose such as glycoproteins (glucose attached with proteins) or glycolipids (glucose attached with lipids) [68]. Glycogen is the reserved form of glucose in animals. Glycogen is broken down to glucose-1-phosphate to enter glycolysis (i.e., glycogenolysis). Contrarily, the molecules of glucose can be converted to glucose-1-phosphate to produce glycogen (i.e., glycogenesis). Blood glucose levels are maintained by two processes: 1) Gluconeogenesis and 2) Glycogenolysis. It is important to maintain blood glucose levels at around 5.5mM. The drop in blood glucose level (>5.5mM), results in hypoglycemia that can cause impairment to brain function and ultimately death if not treated immediately, whereas, very high levels of glucose in the blood over a long period of time can result in diabetes. So, a balance in blood glucose levels is critical for our body to function properly. When blood glucose levels are exaggerated i.e., >140 mg/dL after having a meal then it is referred to as postprandial hyperglycemia. People having postprandial hyperglycemia have insulin resistance, and reduced suppression of hepatic glucose outputs after meals (mainly due to insulin deficiency) [69]. The rate of postprandial blood glucose is regulated by several pathophysiological mechanisms such as insulin secretion, glucagon suppression, and involvement of some intestinal hormones (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1). These mechanisms collectively contribute to normoglycemia in the body after having a meal. There are studies which reveal that about 70% of total daytime hyperglycemia is contributed by postprandial hyperglycemia [70]. The release of insulin in the body occurs in 2 phases. The first phase consists of a release of small amount of insulin for approximately 10 min which is then followed by the y second phase, which includes a more sustained release of insulin which reaches a plateau at 2-3h [71]. The release of insulin in 2nd phase is directly proportional to the glycemic load of the meal. Glycemic load is a function of carbohydrate intake and its glycemic index, as it estimates how much the blood glucose level of a person is increased following an intake of food [69]. There are two enzymes that are responsible for postprandial hyperglycemia i.e. α-amylase and α-glucosidase. Postprandial hyperglycemia can be controlled by incorporating α-amylase and α-glucosidase inhibitors into the diet. These inhibitors retard carbohydrate and glucose absorption and have shown promising results in management of postprandial hyperglycemia. Various polyphenols have shown to inhibit α-amylase and α-glucosidase activity in vitro. So, the presence of polyphenols has attracted a lot of attention as an approach to the management of type-2 diabetes mellitus. Various studies have reported tea to show substantial inhibitor activity against α-amylase and α-glucosidase enzymes [72–74]. Research carried out by Bhatia et al. (2019) indicated that extract from leaves of the Cornus capitata plant has significant inhibitory activity against α-glucosidase enzyme suggesting that it can also be used in the treatment of postprandial hyperglycemia after undergoing further clinical trials [75]. Flavonoids (such as flavonones, anthocyanins, flavones, flavanols and isoflavones), phenolic acids, and tannins (such as proanthocyanidins and ellagitannins) have shown explicit inhibitory activity against α-amylase and α-glucosidase [76]. Food extracts from various berries (such as strawberries, blueberries, raspberries, and black currants), vegetables (such as pumpkins, beans, maize, and eggplant), black rice, green and black tea, and red wine have been reported to show inhibitory activity against α-amylase and α-glucosidase [77]. In another study, crude acerola polyphenols fraction (containing anthocyanins) exhibited inhibition to α-glucosidase [43].

Stimulation of β-cell function

Β-cells are one of the islet cells present in the pancreas where they produce, store, and release the hormone insulin (directly into the bloodstream). These cells swiftly respond to the increasing levels (e.g., during digestion) by secreting stored insulin and increasing the production of insulin. In type-2 diabetes mellitus, there is reduced β-cell sensitivity to glucose, absence of first-phase, and reduced production of insulin in the second phase [78]. Type-2 diabetes mellitus and hyperglycemia cause insulin resistance, which causes the β-cells to generate more insulin to deal with higher blood glucose levels (hyperglycemia). This causes β-cell exhaustion (which may be induced by oxidative stress due to hyperglycemia), resulting in decreased β-cell function as well as a decrease in -cell volume or number. β-cells are prone to oxidative stress due to their low antioxidant capacity this can be avoided with the help of the antioxidant properties of polyphenols. Currently, there is no drug on the market that can restore β-cells to produce normal levels of insulin. After β-cells exhaustion, there is no insulin secretion which is followed by cell apoptosis [79, 80]. When β-cells die, β-cell mass is increased by proliferation, neogenesis, and hyperplasia which is known as β-cell compensation. In type-2 diabetes mellitus, β-cell proliferation and function can be improved and oxidative stress can be reduced by dietary polyphenols having antioxidant properties. Dietary polyphenols like quercetin, epigallocatechin gallate, epicatechin, cyanidin, and morin, have substantial antioxidant properties that can increase β-cell proliferation and functions [45]. Epicatechin, a cocoa polyphenol, has demonstrated excellent antioxidant activity in a number of studies. It prevented cell death in Ins-IE cells that had been pretreated with cocoa phenolic extract when oxidative stress was introduced by i-BOOH (a powerful oxidant) [81].

In another experiment, rat pancreatic cell lines (INS-1) were exposed to polyphenols like gallic acid and quercetin extracted from Crassocephalum crepidioides and alloxan. The results showed decreased levels of intracellular ROS production and a decrease in apoptosis compared to cells only treated with alloxan [82]. Similarly, leaf extracts from Cyclocarya paliurus (polyphenols present:1-caffeoylquinic acid, 5-caffeoylquinic acid, chlorogenic acid, isoquercitrin, kaempferol-3-glucoside, kaempferol 3-rhamnoside, and quercetin) suppresses apoptosis in β-cells of the pancreas.

Attenuation of insulin resistance

Insulin is an anabolic, peptide hormone, secreted from β cells of the pancreas to enhance the absorption of glucose from the blood into various insulin-dependent body tissues. Insulin resistance is a complex situation which is due to the impedance of insulin responsiveness of target tissues (i.e., skeletal muscles (70–80% of glucose), liver, and adipose tissue). This leads to excessive production of insulin leading to impaired function of the pancreas due to oxidative stress [83]. The resistance to endogenous insulin mainly results in type 2 diabetes mellitus, but the other conditions related to IR are obesity, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, metabolic syndrome, and polycystic ovary syndrome (PCOS). In turn, hyperglycemia results in microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (peripheral artery disease, cerebral vascular diseases, and coronary artery disease) complications [84]. Also, a rare genetic defect in the insulin receptors leads to a severe form of insulin resistance which can cause IR syndromes such as Rabson-Mendenhall syndrome, Leprechaunism, and Type A syndrome of Insulin Resistance [45].

The elevated levels of ROS in adipocytes due to mitochondrial dysfunction result in insulin resistance via a decrease in insulin sensitivity. There are two sources responsible for generating excess electrons. The first one is the excess of glucose that derives from the overflow of electrons in mitochondria; the second one occurs in the later stage of obesity in which the uptake of glucose is limited by adipocytes due to insulin resistance. As insulin resistance reduces glucose consumption, the free fatty acids from triglycerides are used by adipocytes for energy. However, this change in source of energy for cells i.e., β-oxidation can devastate mitochondria by steering the leakage of electrons and giving rise to ROS [85].

Polyphenols can act in several ways for mitigation of insulin resistance (demonstrated by various studies done in the past 2 decades) such as IRS protein phosphorylation inhibitors for serine, enhancers for protein kinase B (Akt) phosphorylation, GLUT4 translocation promoters and ROS superoxide scavengers [86, 87]. Also, the gene expression of proteins that are involved in insulin signaling can be improved by polyphenols [45]. The research done has shown that the elevated levels of TNFα and IL-6 (pro-inflammatory makers) are associated with oxidative stress, which can be caused by hyperglycemia or via the stimulation of macrophages due to increased blood glucose levels which ultimately results in insulin resistance [88]. However, the phenolic-rich extract of A. panniculata showed very high antioxidant activity, due to which it showed a very reassuring effect as antidiabetic via improvement in insulin levels, glycolytic enzymes, reduction on the levels of TNFα and IL-6 (proinflammatory markers) and alleviating the oxidative stress and insulin resistance [89].

Advanced glycation end products

Whenever free amino acids of protein get ligated chemically or covalently to a molecule of reducing sugars via an aldehyde or ketone group, it results the in non-enzymatic formation of advanced glycation end products (AGEs) which is an irreversible [90]. It is noted that these AGEs have the potential to damage cells and contribute to diabetic retinopathy, neuropathy, nephropathy, and atherosclerosis [91]. AGEs can interact with different specific and non-specific receptors among which RAGE (Receptor for Advanced Glycation End products) is a prominent receptor [92]. RAGE is a multi-ligand receptor from the IG superfamily which forms the AGE-RAGE complex that can cause the outbreak of metabolic disorders via activation of protein kinase C, transcription factor NF κB, NADPH oxidase, expression of proinflammatory genes (TNFα and IL-6) and intercellular cell adhesion molecule 1 (ICAM-1) [93].

Polysaccharides from different plants such as Polygonum multiforum Thumb, Dendrobium huoshanense, R. idaeus (Rasberry), and Pueraria lobata (roots) have shown the retardation of the glycation process [94]. The extracts of Scutellaria alpina and Scutellaria altissima showed antiglycation activity for the first time [95]. These extracts also showed significant antioxidant activity. Two of the flavones isolated from Scutellaria were baicalin and luteolin which were eminently effective in inhibiting the formation of AGEs [96]. Phagalon lowei, Argyranthemum pinnatifidum, and Helichrysum melaleucum also showed significant anti-glycation activity [97]. In a study to evaluate the role of oat polyphenol over the varying concentrations of AGE’s formation in a BSA Glu (flu) model, the apigenin and luteolin (luteolin > apigenin) were found to be most effective for alleviation of the AGE’s formation [98].

Various dietary polyphenols have exhibited a positive role in the management of diabetes. Table 1 summarizes some clinical studies done on the positive effects of various dietary polyphenols on high blood sugar levels as well as their mechanisms of action. Table 2 lists the various pre-clinical studies that suggest the benefits of polyphenols in reducing elevated blood sugar levels and their mode of action.

Table 1.

Clinical studies suggesting a positive effect of polyphenols on diabetes

S.No.	Polyphenol	Clinical trial result of diabetes	Ref
1	Flavonoid-rich grape seed extracts	A double-blind, randomized, placebo-controlled trial was conducted for 4 weeks on 32 T2D patients (having obesity and higher risk of cardiovascular) administered with flavonoid-rich grape seed extracts resulting in significant improvement in the biomarkers of inflammation, oxidative stress, and glycemia	[99]
2	Flavanol-containing cocoa	A double-masked, randomized, controlled trial reported that daily intake of flavanol-rich cocoa improved the vascular function of T2D patients	[100]
3	Procyanidins and bioflavonoids	A randomized, double-blind, placebo-controlled trial was conducted on 48 T2D patients administered with 12-week daily supplementation of Pycnogenol® (125 mg), which is a French maritime pine bark extract rich in procyanidins and bioflavonoids, might control diabetes, reduce CVD risk factors, and lower antihypertensive medicine use vs controls	[101]
4	Polyphenols and flavonoids from Brazilian green propolis	A double-blind, 8-week randomized controlled study was conducted on 80 T2D patients administered with Brazilian green propolis (226.8 mg/day) rich in polyphenols and flavonoids, resulting in prevention of further development in blood uric acid and estimated glomerular filtration rate	[102]
5	Polyphenols from acacia	A randomized, double-blind, placebo-controlled trial (34 subjects) was conducted and it was revealed that the supplementation of acacia polyphenol (250 mg/day) helps in the regulation of glucose homeostasis in non-diabetic subjects having impaired glucose tolerance	[103]
6	Polyphenols from Coffee	Coffee polyphenols might ameliorate the peripheral endothelial function after glucose intake in healthy male adults	[104]
7	Chlorogenic acids	Coffees containing varying concentrations of chlorogenic acids show the same degrees of effect on glucose/insulin responses in healthy humans	[105]
8	Polyphenols from red wine	A randomized clinical trial was conducted on 67 men having high cardiovascular risk who were administered red wine (polyphenolic rich) observed to have a positive effect on insulin resistance and lipoprotein plasma concentrations	[106]
9	Anthocyanins	A randomized double-blind placebo-controlled clinical trial was conducted on 37 T2D patients administered with anthocyanin-rich whortleberry extract resulted in a significant reduction in the levels of fasting blood glucose, 2-h postprandial glucose, and HbA1c	[107]
10	Polyphenols from chocolate	A double-blinded randomized controlled study was conducted on T2D patients supplemented with chocolate having high-polyphenol resulted in protection against endothelial dysfunction and oxidative stress during acute transient hyperglycemia, induced by a 75-g oral glucose	[108]
11	Polyphenol-rich extra-virgin olive oil	It was reported that in overweight T2D patients, daily consumption of polyphenolic-rich extra-virgin olive oil might improve metabolic control and the profile of circulating inflammatory adipokines	[109]
12	Guava tea rich in polyphenols	Polyphenolic-rich guava tea lowers blood glucose levels, by inhibiting the digestion of sugars in the gastrointestinal tract	[110]
13	Polyphenols from E. punicifolia	A pilot noncontrolled study was conducted in which a 3-month treatment with powdered dried leaves of E. punicifolia resulted in a significant reduction of glycosylated hemoglobin and basal insulin levels	[111]
14	Rutin	Rutin-rich aqueous extract (0.15% infusions) of Bauhinia forficata (L) subsp. pruinosa (Fabaceae), might significantly reduction in HbA1c concentration in diabetic and pre-diabetic volunteers (n = 15)	[112]
15	Quercetin,	A randomized, double-blinded, placebo-controlled, cross-over trial was conducted on 22 healthy males who were administered with 500 mg quercetin, found that the treatment had no effect on the fasting glucose	[113]
16	Catechins	A meta-analysis of randomized controlled trials showed that tea catechins might significantly lower fasting blood glucose	[114]
17	Curcumins	A study was conducted on patients with T2DM, to examine the anti-atherosclerosis effect of curcumin. Curcuminoid supplementation (1,000 mg/day) for 12 weeks might decrease the serum levels of atherogenic lipid levels, HDL, and lipoprotein Further, another recent clinical trial conducted on T2DM also showed that curcumin supplementation of curcumin (1,000 mg/day) for 12 weeks resulted in higher adiponectin level and lower leptin concentration, with decreased leptin/adiponectin ratio (a measure of atherosclerosis)	[115]
18	Procyanidins and bioflavonoids	A study showed that administration of procyanidins and bioflavonoids might control diabetes and CVD risk factors	[101]
19	Coffee polyphenols	Coffee polyphenols might improve peripheral endothelial function after glucose intake in healthy male adults	[104]
20	High-polyphenol chocolate	In T2D, during acute transient hyperglycemia, treatment with high polyphenolic chocolate resulted in protection against endothelial dysfunction and oxidative stress	[108]
21	Flavanol-rich foods (wines), procyanidins	Flavanol and procyanidin-rich food have the potential of inhibit angiotensin-converting enzyme activity	[116]
22	Grape seed-derived polyphenol extract	In human male smokers, Polyphenolic grape seed extract might help in reduction of oxidation susceptibility of LDL	[116]
23	Total polyphenols, lignans, flavonoids and hydroxybenzoic acids	It has been observed that intake of total polyphenols, lignans, flavonoids, and hydrobenzoic acids by older ages and high-risk cardiovascular people could lower the risk of CVD	[117]
24	Hesperidin	A randomized cross-over clinical trial was conducted in which, oral administration (50 mg/d for 3 weeks) of hesperidin, a citrus flavonoid, led to an increase of flow-mediated dilation and reduction of circulating inflammatory biomarkers (hs-CRP, serum amyloid A protein, soluble E selectin), and decreased adhesion of monocytes, expression of vascular cell adhesion molecules-1 and also regulate vascular function in patients of metabolic syndrome	[116]
25	Isoflavones from red clover	In postmenopausal type 2 diabetic patients, it has been observed that 4 weeks of supplementation of red clover (50 mg/day) rich in isoflavones improved endothelial function and lowered systolic and diastolic blood pressure	[118]

Table 2.

Pre-clinical studies suggesting positive effect of polyphenols on diabetes

S.No.	Polyphenol	Pre-clinical trial result of polyphenols on diabetes	Ref
1	Green tea polyphenols, mainly catechins and epicatechins	They have been shown to decreased hyperglycemia and hepatic glucose output by downregulating the expression of liver glucokinase and upregulating the PEPCK	[119]
2	Epigallocatechin gallate (EGCG)	In Vitro study performed, it is shown that EGCG activates AMP-activated protein kinase as a required pathway for the inhibition of expression of gluconeogenic enzymes	[120]
3	Quercetin, resveratrol and EGCG	They regulate insulin-dependent glucose uptake in muscle cells and adipocytes by translocation of glucose transporter, GLUT4, to plasma membrane via induction of the AMP-activated protein kinase (AMPK) pathway	[121]
4	Isoflavones, particularly genistein,	Genistein acts as a novel agonist of cyclic AMP/protein kinase signalling pathway, and an important physiological amplifier of glucose-induced insulin secretion through pancreatic β-cells	[122]
5	Resveratrol	In vitro studies revealed that resveratrol can reduce insulin secretion via induction of metabolic changes in β-cells thus delaying the degradation of pancreatic islets and the progress of type 2 diabetes	[123]
6	Anthocyanins	Anthocyanins-rich Chinese bayberry extract has protective effects for pancreatic β cells against oxidative damage via up-regulation of heme oxygenase-1, modulation of ERK1/2 and PI3K/Akt signaling pathway and inhibition of β cells apoptosis	[118]
7	Cyanidin 3- glucoside	Purple corn extract rich in cyanidin 3- glucoside and cyanidin-3-(6″-malonylglucoside) helps in reduction of hyperglycemia-induced mesangial cell proliferation and matrix accumulation, and also prevents over-expression of intracellular cell adhesion molecule-1 and monocyte chemoattractant protein-1, as major features of diabetic mesangial fibrosis and glomerulosclerosis	[118]
8	Phenolic acids (Chlorogenic and ferulic acids)	They have been shown to upregulate the expression of glucose transporter GLUT2 in pancreatic β-cells and facilitate the translocation of GLUT4 via PI3K/Akt and AMP activated protein kinase pathways	[124]
9	Quercetin	Hike in glucose uptake in rat adipocyte, C2C12 muscle cells,	[125]
10	Rutin	Hike in glucose uptake in the rat soleus muscle	[126]
11	Isorhamnetin	Reduces hyperglycemia and oxidative stress in STZ-induced diabetic rats and inhibits adipogenesis in 3 T3-L1 cells	[127, 128]
12	Kaempferol	Reduces hyperglycemia by increasing Glucose uptake in rat soleus muscle and increased β-cell survival in INS-1E cells	[125]

Cardiovascular protective effects of polyphenols

Polyphenols are plant-based secondary metabolites having antioxidant, vasodilatory, and immunomodulatory properties which are beneficial against cardiovascular diseases [129]. More than 80,000 polyphenols have been identified in plants [130]. Tea, coffee, olive, cocoa, and berries are some examples of sources of polyphenols. Polyphenols have a common phenolic hydroxyl group and differences in primary aromatic rings, functional groups, and oxidation status. The antioxidant property of polyphenols is due to their hydroxyl groups [131]. They have been classified into four classes viz flavonoids, lignans, phenolic acids, and stilbenes. Various polyphenols are known to possess cardiovascular effects. For example, Polyphenols found in apples, cacao, Lily bulbs, red wine, grape, chokeberry, olive oil, and tea [42, 132–137]. have been shown to exhibit cardiovascular protective effects. We have discussed various studies that reveal the role of Polyphenols in attenuating the CVCs along with their targets in the following sub-headings:

Lipid metabolism

Blood lipids play a major role in the progression of cardiovascular diseases. Decreased levels of high-density and conversely increased levels of low-density lipoprotein cholesterol, total cholesterol, and triacylglycerol are related to increased CVDs [138]. There are many studies conducted on polyphenolic compounds and their effects on lipid metabolism. Apple has high polyphenolic content and studies conducted in the UK have shown positive results of apple polyphenols in the attenuation of CVDs [132]. Cacao polyphenols have been shown to inhibit the oxidation of low-density lipoproteins and cholesterol and prevent fat accumulation in the liver [136]. Cacao polyphenolic-rich diet, forms very small and short lipid droplets, thus preventing the accumulation of lipids [136]. Experiments done in mice models have shown that a high-fat diet mixed with phenolics upregulates the activity of the beta-oxidation enzyme [139]. Lily bulb’s phenols (LBPs) have shown potential in the prevention of metabolic syndrome by reducing the level of oxidative stress, reducing lipid accumulation, controlling the body weight, maintenance of lipid levels in serum and liver, and improving oxidative damage [137]. LBPs prevent steatosis and suppress the expression of hepatic-lipogenesis-related genes and transcription factors viz., SREBP-1c (Sterol regulatory element-binding transcription factor-1), FAS (fatty acid synthase), SCD-1 (stearoyl-coenzyme A desaturase) and ACC1(Acetyl-CoA carboxylase) [137]. LBPs elevate lipolysis genes and lipid oxidation genes [137].

Blood pressure and blood coagulation

Blood pressure is an important parameter of the cardiovascular system and polyphenols have shown significant potential in the regulation of blood pressure. Here, we have compiled the studies and reports of some polyphenols and their effects in maintaining blood pressure or alleviating hypertension. The evidence of a decrease in blood pressure in rats upon the administration of red wine polyphenolic compounds (RWPC) can be helpful in high blood pressure patients [42]. The grape has polyphenols, such as anthocyanins, flavonols, flavanols, and phenolic acids [133]. Experimental studies have shown that grape polyphenols can increase the bioavailability of nitric oxide (NO), improve insulin sensitivity, and decrease the thickness of blood and thus can reduce systolic blood pressure [95]. Aronia Chokeberry is rich in anthocyanins, proanthocyanidins, chlorogenic acids, quercetin and flavonones, and polyphenolic compounds [135]. It has been experimented that chokeberry polyphenolic consumption has a positive effect on blood pressure. Thus, it can be a used as promising agent to decrease cardiovascular risks [48]. It was investigated in Stroke-Prone Spontaneously Hypertensive Rats, that tea polyphenols can reduce hypertension by alleviation of oxidative stress [140]. Tea polyphenols increase the bioavailability of NO which can ameliorate hypertension and upregulate the catalase enzyme which scavenges H₂O₂ [141]. It is also reported that Olive oil phenols can decrease blood pressure in hypertension [134].

Vascular function

The regulation of vascular function is coordinated by many cell components. It includes vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and adventitial tissues along with inflammatory and immune cells [142]. All these cells/tissues interact and coordinate to maintain vascular function. Oxidative stress contributes to ECs dysfunction and VSMCs proliferation. It is experimented that resveratrol (phenolic compound) increases the production of NO via upregulation of eNOS and decreases the formation of endothelin-1 [143]. It inhibits the VSMCs proliferation, arterial stiffness, and vascular remodeling. It modulates immune cell function and thus has a protective role in maintaining vascular function [143]. It was also demonstrated that polyphenolic compounds prevent PM (particulate matter) induced pro-inflammation and migration in VSMCs [144].

Postprandial state and atherosclerosis

The majority of the time is spent in the postprandial state, which is the period following a meal. It is a complex state as physiological reactions and metabolism occur in this period [145]. The postprandial state’s time period depends upon the type of meal. Postprandial dysmetabolism is characterized by an increase in the levels of glucose which is responsible for the development of cardiovascular complications. In postprandial glycemia and lipemia, the duration gets prolonged which leads to oxidative stress, coronary heart disease, inflammation, atherosclerosis, and endothelial dysfunction [146]. In postprandial glycemia and lipemia, there is an increase in the production of TRP (triglyceride particles) from two sources, one is endogenous i.e., liver through VLDL particles, and the other from exogenous i.e., intestine through chylomicrons [147]. Postprandial hyperglycemia activates the excessive production of superoxide anion that activates NF-κB, decreases NO production, and increases the expression of pro-inflammatory cytokines and pro-coagulants which collectively favors the formation of atherosclerosis [134]. Experiments have shown that polyphenolic-rich diets reduce the concentrations of plasma triglyceride in large VLDL in fasting as well as postprandial states [148]. Research studies also indicate that a high polyphenolic-rich diet reduces VLDL and ILDL cholesterol [149].

Coronary heart disease

Coronary heart disease (CHD) or coronary artery disease is a condition in which the major blood vessels supplying the heart get narrowed which reduces the flow of blood. This leads to reduced blood flow which can cause breath shortness and chest pain [150]. In CHD, there are alterations in the normal functioning of endothelial cells, heart muscle cells, blood cells (monocytes and platelets), smooth muscle cells, blood vessels, and plasma components (fibrinogen, clotting factors, etc. [151]. Polyphenolic compound cichoric acid obtained from C. intybus having nephroprotective and cardioprotective properties was investigated on rats and it has shown positive results on the treatment of myocardial ischemia and acute renal failure [47]. Mediterranean diet rich in extra virgin olive oil has positive results in reducing CHD as compared to a low-fat diet [65]. It is demonstrated that because of the presence of polyphenols catechins, chlorogenic acid, and theaflavin in tea and coffee, their regular consumption has beneficial effects on coronary heart diseases [46].

Numerous studies have demonstrated that polyphenols are effective in managing cardiovascular complications. Table 3 lists several classes, subclasses, and specific compounds that demonstrate the beneficial effects of various dietary polyphenols in the reduction of cardiovascular-associated complications.

Table 3.

Positive effects of different polyphenols in attenuating the cardiovascular complications

S.No.	Class of Polyphenols	Sub class of Polyphenols	Specific polyphenols	Effect on Cardiovascular complications	Ref
1	Flavonoids		Artemetin	Increases eNOS-dependent NO production in porcine aortic endothelial cells	[152]
			Nobiletin	Inhibits collagen-induced fibrinogen binding to its receptor	[153]
		Anthocyanidins	Anthocyanin glycosides	Promotes vasodilation	[154]
			Delphinidin aglycone	They are reported to induce endothelium-dependent vasodilatation in aorta in mice through activation of ER-α	[155]
			Delphinidin, cyanidin aglycone	Inhibit ET-1 synthesis in HUVECs, with a simultaneous increase in eNOS expression	[156]
			Delphinidin glycosides	They are reported to inhibit the activity of vasoconstrictors, such as	[157]
			Delphinidin-3-O-rutinoside	Promotes vasodilation via stimulation of ETB receptors and the cGMP pathway and exerted an inhibitory effect on ET-1 induced contraction in bovine ciliary smooth muscle	[156]
			Delphinidin-3-O-glucoside	Inhibits platelet aggregation	[158]
			Pelargonidin aglycone	Inhibits thrombin-induced fibrin polymerization and platelet aggregation	[159]
		Isoflavones	Genistein and Daidzein	Ameliorates endothelial function	[160]
		Flavones	Apigenin	Inhibits the lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages, such as NF-κB, MAPK/ERK, and JNK pathways	[128]
			Luteolin	Inhibits oxidized LDL and TNF-α-induced VCAM-1 expression, as well as suppression of the IκBα/NF-κB signaling pathway	[161]
		Flavonols	Quercetin	Inhibits collagen-induced fibrinogen binding to its receptor	[162]
		Flavanones	Hesperetin, naringenin, naringin	Reduces inflammation by decreasing VCAM-1 expression	[163]
2	Phenolic acids	Hydrobenzoic acids	Gallic acid	Inhibits platelet aggregation, anti-hypertensive effect and anti-inflammatory	[164]
			Protocatechuic acid	Increases endothelium-dependent vasodilation	[165]
			Hippuric acid	Inhibits platelet aggregation	[166]
		Chlorogenic acid		Increases NO production and heme oxygenase-1 (HMOX-1) induction, improves endothelial function by antioxidant, anti-inflammatory and ACE inhibitory effect	[167]
		Hydroxycinnamic acids	Caffeic acid	Showed vasorelaxation effect in both aging and spontaneously hypertensive rats, increases basal and acetylcholine induced NO release, independent of eNOS phosphorylation and expression	[168]
			Ferulic acid	Improves vascular function, endothelium independent vasorelaxation effect on aging and spontaneously hypertensive rats	[169]
			Rosmarinic acid	Ameliorates cardiac dysfunction and fibrosis, restore cardiac function and decrease myocardial infarct size	[170]
			Vanillic acid	Improves ventricular function in ischemia/reperfusion subjected isolated rat heart, anti-inflammation effect	[168]
			Syringic acid	Prevents myocardial damage by regulating oxidative stress, besides downregulating circulating pro-inflammatory cytokines, IL-6 and TNF-α	[171]
			Ellagic acid	Exhibits anti-atherogenic effect via reducing THP-1 monocytes adhesion to HUVECs and decrease sVCAM-1 and IL-6 secretion, reduce the accumulation of cholesterol in THP-1-derived macrophages	[172]
3	Stilbenes		Resveratrol	Acts as a vasodilator through via enhancing endothelial NO production, increases eNOS expression in mouse arteries, improves endothelial dysfunction	[173]

Polyphenols used in both diabetes and CVD

The polyphenols are strongly supported by evidence from various preclinical and clinical as an efficient therapeutic agent with the multitargeted approach as provided in Tables 1, 2 and 3. There is evidence from various studies suggests that polyphenols such as quercetin, chlorogenic acids, ferulic acids, genistein, resveratrol, and various anthocyanins have anti-hyperglycemic potential as well as a protective function against cardiovascular complications. (Fig. 7) Various studies have reported and confirmed the role of the structure–activity relationship of these polyphenols responsible for their substantial antioxidant, antidiabetic, and cardioprotective activities. For instance, quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one), is a main dietary flavonoid with five hydroxyl groups at positions 3,5,7,3, and 4' in its basic structure. (Table 4) It is the most potent antioxidant among flavonoids, which may be due to the OH group in the B- and C-rings [174]. Quercetin exhibited the highest EC₅₀ (EC₅₀: 8.93 0.44 mol/L, p < 0.05) and CAA values in the cellular antioxidant assay. Structure–activity studies suggested the substantial activity may be due to the presence of a 3′,4′-o-dihydroxyl group [175]. Further, it exhibited stronger free radical scavenging activity due to the presence of a hydroxyl group at position C-3 [176]. Shamsudin et al., (2022) [177] proposed the α-glucosidase and DPP-4 inhibitory activity may be due to the catechol group (hydroxyl groups at positions C3′ and C4′ of the B-ring). Quercetin-3-O-glucuronide and 3′-O-methyl-quercetin have been shown to activate eNOS in human aortic endothelial cells, according to research (HAECs) [178].

Fig. 7.

Polyphenols used in management of diabetes and CVD

Table 4.

Chemical structure of quercetin, resveratrol, and genistein

Chlorogenic acid (CGA) is an ester of caffeic acids with quinic acids [179]. CGA is a catecholic acid and its bioactivities may be due to the presence of phenolic groups [180]. In microsomes of rat liver, chlorogenic acid was discovered to be a selective inhibitor of the glucose-6-phosphate translocase component (Gl-6-P translocase) of the enzyme system glucose-6-phosphatase (EC 3.1.3.9) [181]. It helps attenuate cardiovascular complications by reducing LDL oxidation susceptibility, lowering LDL cholesterol, and lowering levels of malondialdehyde (MDA) [182]. Resveratrol is natural non-flavanoid phenol and a phytoalexin [183]. It is a stilbene derivative (3,4′,5-trihydroxy-trans-stilbene), (Table 4) commonly found in red wine and grapes [184]. It has various properties viz., antioxidative, antiproliferative, anti-inflammatory, anti-carcinogenic, anti-diabetic, anti-aging, antiviral, and neuroprotective [185, 186]. Due to the presence of the p- 4′-OH group, it shows antioxidant properties [185]. It increases the amount of glycogen in the liver by activating glycogen synthase and blocking glycogen phosphorylase. Hepatic glucose production is decreased as a result of these alterations [40]. Resveratrol inhibits the catalytic activity of the Angiotensin-converting enzyme(ACE) via interacting with amino acids at the active site [187]. Genistein is 5,7-dihydroxy-3-(4-hydroxyphenyl) chromen-4-one. (Table 4) It is a natural isoflavonoid and phytoestrogen. It has anti-cancerous, anti-inflammatory, and cardio-protective [188]. Its estrogen-like activity is due to the presence of C4 and C7 on the phenol rings [189]. The anti-hyperglycemic activity of genistein is due to the presence of the 4’OH active group [95]. Genistein inhibits the activation of NF-κB (an important transcription factor for iNOS), prostaglandins(PGs), and ROS thus exhibiting anti-inflammatory activity [188]. It has a hypocholesterolemic effect on animals and humans. It inhibits LDL oxidation, endothelial cell proliferation, and angiogenesis. Thus acts as a potent cardio-protective compound [190]. Ferulic acid (4-hydroxy-3-methoxycinnamic acid, or FA) is found in a variety of plants, including grasses, grains, vegetables, flowers, fruits, leaves, beans, seeds of coffee, artichokes, peanuts, and almonds, as well as commelinid plants (rice, wheat, oats, and pineapple) [191, 192]. Its strong antioxidant properties are due to the resonance stabilized phenoxy radical. It also exhibits antioxidant activity by transferring one hydrogen atom from its phenolic hydroxyl group in response to free radicals [191]. Due to reduced oxidative stress, the β-cells of the pancreas proliferate and release more insulin. In a study, it has been demonstrated that FA (1–100 mg/kg body weight) taken orally for two hours reduced blood pressure in both SHRSP (stroke-prone spontaneously hypertensive) rats and SHR (spontaneously hypertensive rats), with the largest effect (34 mmHg) occurring at that time [191]. By altering the activity of the key factors involved in angiogenesis, including platelet-derived growth factor (PDGF), hypoxia-inducible factor 1(HIF-1), and vascular endothelial growth factor (VEGF), ferulic acid is thought to have angiogenesis-inducing effects [192]. Further research needs to be done to determine the ability of other polyphenols to prevent hyperglycemia and CVD.

Discussion

The preclinical and clinical reports published show undoubtedly substantial role of polyphenols in the attenuation of diabetes and diabetes-induced cardiovascular complications (summarized in Tables 1 and 2). The substantial activity displayed by these polyphenols is mainly based on the amount of their consumption and bioavailability. Polyphenols are known to exert beneficial actions on the vascular system via blocking platelet aggregation, oxidation of low-density lipoprotein, amelioration of endothelial dysfunction, reducing blood pressure, improving antioxidant defenses, and improving inflammatory responses. Further, resveratrol, a natural compound exhibits anti-oxidant activity, anti-inflammatory activity, islet cell protective activity, increased mitochondrial performance, regulates lipid metabolism, triggers autophagy, and other mechanisms. By regulating several signaling pathways, including the SIRT1 and AMPK signaling pathways, resveratrol can reduce diabetes and cardiovascular problems [193]. Quercetin exhibits significant anti-diabetic activity because it modulates various factors and signaling pathways involved in insulin resistance and in the development of T2DM. It regulates factors including TNF, NFKB, AMPK, AKT, and NRF2 [194]. Several polyphenols such as resveratrol, epigallocatechin gallate (EGCG), honokiol, curcumin, quercetin, oleuropein, baicalein, salvianolic acid, target proteins such as mTOR (a serine/threonine-specific protein kinase) which plays a vital role in the progression of cardiovascular complications such as atherosclerosis, cardiac hypertrophy, and heart failure, etc. [195]. According to research findings, quinoa supplementation at dosages more than 50 g/day and an intervention period longer than 6 weeks considerably reduced triglyceride levels [196]. Sesame oil reduces serum alanine aminotransferase, aspartate aminotransferase levels, and the severity of the fatty liver in women with nonalcoholic fatty liver disease who are on a low-calorie diet [197]. Its consumption significantly reduced FBG, HbA1C, MDA, BMI, and body weight [198]. Polyphenols and carotenoids modulate endothelial dysfunction biomarkers through the attenuation of inflammation and oxidative stress, thus improving endothelial function, blood pressure, platelet activity, and insulin sensitivity [199]. Morin and Quercetin exhibit endothelial protective activity through different signaling pathways. While Quercetin encourages eNOS activation, NO generation, and vascular relaxation in the DM aorta via PI3K/Akt and AMPK signaling, Morin does the same through Akt signaling independent of PI3K and AMPK [200]. Berberine demonstrates a vasodilatory effect via increasing intracellular cGMP in vascular smooth muscles and this effect is prolonged by releasing EDRF from arterial endothelium. Berberine lowers blood pressure by blocking calcium channels and vasodilates arteries by inducing nitric oxide [201].

Conclusions and future prospects

Diabetes mellitus is an unabated metabolic health exigency emerging in the modern world. Polyphenols are recognized widely for possessing a variety of therapeutic properties, including anti-diabetic potential. One of the major health problems associated with DM is cardiovascular complications that are responsible for high morbidity and mortality. The present review provides an insight into the protective role of polyphenols in attenuating cardiovascular complications such as atherosclerosis, disorders related to vascular function, coronary heart disease, etc. This review also focuses on the anti-hyperglycemic effects exhibited by various dietary polyphenols. Further research needs to be done on the molecular level to ascertain the anti-diabetic and cardio-protective function of polyphenols. Moreover, the actual mechanisms by which different polyphenols are metabolized in the body need to be elaborated. In order to increase the efficacy of polyphenols against DM and CV complications, it is crucial to explicate the factors which reduce the bioavailability of polyphenols and renders them less effective.

Author contributions

AB, SA and BS designed the concept of the manuscript. NK wrote the sections on sources, bioavailability, metabolism and antihyperglycemic potential of polyphenols. GB wrote the sections on oxidative stress, inflammation in diabetes and cardiovascular protective effects of polyphenols. SS wrote the sections on antioxidative properties of polyphenols and designed the figures. SSB revised and completed the final manuscript. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

Not applicable.

Declarations

Ethical approval

Not applicable.

Competing interest

The authors have no relevant financial or non-financial interests to disclose.