Review Not peer-reviewed version

The Multifaceted Actions of

Polyphenols in the Management

of Type-2 Diabetes Mellitus

*
Ileana González , Cristian Lindner , Ivan Schneider , Erik Diaz , MIguel A. Morales , Armando Rojas

Posted Date: 3 July 2023

doi: 10.20944/preprints202307.0110.v1

Keywords: type-2 diabetes mellitus; polyphenols; oxidative stress; antioxidant capacity

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Review

The multifaceted actions of polyphenols in the man-

agement of type-2 diabetes mellitus.
Ileana Gonzalez 1, Cristian Lindner 2, Ivan Schneider 3, Erik Diaz 4, Miguel A. Morales 5 and Ar-
mando Rojas 1*
1 Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca, Chile
2 Department of Radiology, Faculty of Medicine, University of Concepcion, Concepcion, Chile.
3 South Metropolitan Health Service, Santiago, Chile.
4 Medicine Faculty, Catholic University of Maule, Talca, Chile.
5 Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santi-

ago, Chile
* Correspondence author at : arojasr@ucm.cl .

Abstract: Type-2 diabetes mellitus is recognized as a serious public health concern with a consider-
able impact on human life, the long-term health expenditures, and substantial health losses.In this
context, the use of dietary polyphenols to prevent and manage Type 2 diabetes mellitus is widely
documented. These dietary compounds exert their beneficial effects by several actions, including
the protection of pancreatic islet β-cell, the antioxidant capacities of these molecules, their effects on
insulin secretion and actions, the regulation of intestinal microbiota, and their contribution to ame-
liorate diabetic complications, particular those of vascular origin. In the present review, we intend
to highlight these multifaceted actions and the molecular mechanisms by which these plant-derived
secondary metabolites exert their beneficial effects on type-2 diabetes patients.

1. Introduction.
Diabetes mellitus is a heterogeneous group of chronic metabolic disorders characterized by hy-
perglycemia resulting from defects of insulin action, insulin secretion, or both [1].
This metabolic disease is a global health issue, which has been increasing from time to time and
it is now considered as one of the most important disorders worldwide. According to International
Diabetes Federation, 10.5% of adults of the world population are currently living with diabetes and
this alarming indicator is predicted to rise to 11.3 %, (643 million people) by 2030 and to 12,2 % (783
million) by 2045 [2].
Noteworthy, a considerable proportion of the world's burden of diabetes is caused by type 2
diabetes mellitus (T2DM). In this regard, T2DM is recognized as a serious public health concern
with a considerable impact on human life and health expenditures [3].
The onset and progression of T2DM are determined by a complex pathophysiological basis
where oxidative stress is a crucial contributor not only involved in the disease development but also
to diabetes complications, particularly those associated with both microvascular (retinopathy,
nephropathy, and neuropathy) and macrovascular complications (ischemic heart disease, peripheral
vascular disease, and cerebrovascular disease [4].
Acute or chronic hyperglycemia upregulates ROS production in the mitochondrial electron
transfer chain. This excessive production of superoxide an inorganic radical anion mediates the
downregulation of GADPH levels, which in turn activates the major pro-oxidative pathways in-
volved in the pathogenesis of diabetes complications, such as the activation of protein kinase C, the

© 2023 by the author(s). Distributed under a Creative Commons CC BY license.

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polyol and hexosamine pathways, the formation of advanced glycation end products production
(AGEs), as well as the increased expression of the receptor for AGEs [5-7].
On the other hand, antioxidant mechanisms are diminished in diabetic patients, which may fur-
ther augment oxidative stress [8-10].
During the last few years, compelling shreds of evidence have shed light on the usefulness of
dietary antioxidants as an alternative option in the treatment of T2DM, considering both the adverse
effects conferred by conventional pharmacological treatments as well as the enormous economic bur-
den that lifelong treatments place on patients [11].
In this regard, dietary polyphenols have emerged as an option to manage T2DM. These com-
pounds are one of the most abundant secondary plant metabolites, which are grouped into four major
families, flavonoids, ligands, stilbenes, and phenolic acids, and are widely found in fruits, vegetables,
nuts, cereals, and in many beverages such as tea, coffee, and red wines. A growing body of experi-
mental and clinical evidence supports the protective role of these compounds on several human dis-
eases through their antioxidant activity and diverse molecular mechanisms [12-16].
This review is aimed to highlight the roles of this large and heterogeneous family of secondary
metabolites of plants containing phenol rings, on pancreatic islet β-cell functioning and promotion of
insulin production and signaling, protection against micro-and microvascular complications, protec-
tion against the progression of T2DM-associated obesity, management of dyslipidemia and gut mi-
crobiome dysbiosis. In addition, the capacity of polyphenols to reduce both the formation of ad-
vanced glycation products and their pathologic consequences is also addressed.

2. β-cell dysfunction and death.

Currently, both clinical and experimental data support that during the development of T2DM,
there is not only a progressive deterioration in β-cell functioning but also a marked reduction of the
β-cell mass in the pancreatic islets of Langerhans [17-19].
Many factors such as the glucotoxicity associated with the hyperglycemic state, the oxidative
and endoplasmic reticulum stresses, as well as the lipotoxicity due to chronic exposure to saturated
free fatty acids (FFA), are crucial elements in decreased beta-cell functioning and, eventually in β cell
death through apoptosis [17,20,21].
Hyperglycemia is a crucial factor in the onset of oxidative stress in T2DM and it even correlates
with the progression of disease [22]. Additionally, β-cells are very susceptible to oxidative damage,
because of their low antioxidant capacity [23,24], and consequently, oxidative stress is a very im-
portant contributor to the impairment of beta-cell functioning [21,25,26]. Furthermore, oxidative
stress mediates the permeabilization of mitochondrial membranes, and consequently the release of
cytochrome C and thus β-cell death by apoptosis [27].
Based on their antioxidant activities polyphenols are major regulators of oxidative stress and
consequently the improvement of mitochondrial functions. Cocoa catechins can also improve insulin
secretion by increasing the expression of some genes involved in mitochondrial respiration [28].
Resveratrol is known for its remarkable activities in improving pancreatic β-cell function mainly
by its effect on Sirtuin-1, a master regulator for β-cell function [29]. Cinnamic acid derivatives can
improve the insulin-secreting capacity of beta-cells, by raising the levels of intracellular calcium [30].
Noteworthy, compelling pieces of evidence support that the hyperglycemia-associated overex-
pression of human amylin, also known as islet amyloid polypeptide (IAPP), can form aggregates to
favor amylin fibril formation, and these fibrils evoke the activation of caspases cascade and thus lead-
ing to β-cell death by apoptosis [31,32].
Several polyphenols such as rosmarinic acid, ferulic acid, epigallocatechin gallate, and resvera-
trol, among many others, can interfere with the formation of fibrillar structures and thus avoid β-cell
death [33,34].
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3. Insulin resistance.
Insulin receptor (IR) is a tyrosine kinase receptor, which is autophosphorylated upon insulin
binding and it is expressed in all tissues. The major responders to IR engagement by insulin are the
liver, skeletal muscle, and adipose tissue [35].
Upon insulin binding complex signaling is activated including several substrates such as insulin
or insulin-like growth factor (IGF)-1, insulin receptor (IR), insulin receptor substrate (IRS)-1, and
phosphatidylinositol-3 kinase (PI3-K)/Akt or ERK kinases. The phosphorylation of IRS1 can recruit
PI3K rendering Akt phosphorylated, which in turn can regulate crucial events such as the transloca-
tion of glucose transporter GLUT4 to the cell surface, promoting glycogen synthesis through inhibi-
tion of GSK3 activity, the induction of protein synthesis via activation of mTOR and the inhibition
of FoxO transcription factors [36,37].
The inactivation of Akt and activation of FoxO1, through the suppression of IRS1 and IRS2 in
different organs following hyperinsulinemia, over-nutrition, and inflammation, represent crucial
mechanisms for insulin resistance in humans [38,39].
Compelling shreds of evidence support that oxidative stress is an important contributor to insu-
lin resistance in T2DM [40], and that the production of mitochondrial H2O2 [41,42], and the overac-
tivation of NAPDPH oxidase, via angiotensin II/AT1 receptor can mediate skeletal muscle insulin
resistance [43]. Furthermore, oxidative stress has been shown to impair insulin signaling through the
reduction of the activity of tyrosine phosphatase which in turn, raises the basal level of tyrosine phos-
phorylation in both the insulin receptor and downstream proteins involved in the signaling cascade
[44,45].
The cJun-N-terminal kinases (JNKs) is major signal transducer driving the physiological re-
sponse to several cellular stressors, including oxidative stress. Epigallocatechin gallate, the major
green tea catechin can protect both the insulin receptor and IRS proteins from phosphorylation by
JNKs, a crucial event in the onset of insulin resistance [46], as well as by reducing the expression of
the negative regulator of insulin receptor PTP1B [47].
Resveratrol, which is one of the main polyphenolic compounds of red wines, peanuts and ap-
ples, is a potent activator of sirtuin 1 (SIRT1), which is a potent intracellular inhibitor of oxidative
stress, and thus attenuates insulin resistance and improves insulin signaling in the skeletal muscle
cells [48,49].

4. Obesity.
Obesity is the major driving factor of T2DM and it is characterized by chronic low-grade inflam-
mation with permanently increased oxidative stress [50,51]. The onset of a chronic condition of oxi-
dative stress in obesity is supported by different mechanisms implicated in the homeostasis of adi-
pose tissue, which contributes to the development of pathological systemic consequences [52]. On
one hand, those associated with increased reactive oxygen species (ROS) production such as the adi-
pocytes-associated endoplasmic reticulum stress, a sustained increase of NOx activities, as well as
the high level of post-prandial-associated ROS generation, and on the other, the altered antioxidant
defenses observed in obese patients [53-56].
In addition to the antioxidant properties of polyphenols, they exert several beneficial effects on
obesity far beyond their antioxidant capacity [57], such as the attenuation of obesity-linked inflam-
mation [58], the beneficial regulation of several key obesity pathways such as the modulation of food
intake [59], the inhibition of pancreatic lipase [60]; decreasing lipogenesis by inhibiting both fatty
acid synthase activity and the activation of the adenosine monophosphate (AMP)-activated protein
kinase (AMPK) [61,62], and by increasing thermogenesis and mitochondrial biogenesis [63].
Finally, some polyphenols have been reported to mediate the suppression of the conversion of
preadipocytes into adipocytes, which can store an excessive lipid load. This polyphenols-mediated
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suppression of adipocytes differentiation occurs by the regulation of crucial factors such as C/EBPα,
PPARγ1, PPARγ2, and GLUT-4 in mature adipocytes [61,64,65].

5. Dysbiosis
Human gut microbiota is considered a complex microbial ecosystem composed of different mi-
croorganisms, including bacteria, archaea, viruses, fungi, and protists, which are involved in the reg-
ulation of many physiological processes and numerous diseases [66].
Firmicutes and Bacteroidetes are the main phyla that composed the adult gut flora, regulating
the homeostatic production of microbiota-induced metabolites such as butyrate, which have anti-
inflammatory and antioxidative properties, and the production of lipopolysaccharide (LPS), which
can promote systemic inflammation and insulin resistance through induction of metabolic endotox-
emia [67,68].
Growing data raised from both clinical and experimental evidence shows that T2DM patients
have an altered gut microbiota, where the Bacterioidetes/Firmicutes ratio of the intestinal flora of
diabetic patients significantly differs from non-T2DM adults [69,70].
A crucial consequence of the quantitative change in gut microbiota composition in T2DM pa-
tients is the impairment of the expression of gut-microbiota-related metabolites, which have crucial
consequences in the metabolic regulation of glucose homeostasis, and insulin sensitivity [70].
Short-chain fatty acids (SCFAs) are considered one of the main microbial metabolites, that have
crucial effects on the expression of glucagon-like peptide-1 (GLP-1) and GLP-2 via stimulating G-
protein-coupled receptors (GPR), thus contributing to improve glucose homeostasis and amplifica-
tion of insulin sensitivity [71].
Under this dysbiosis condition that affects T2DM patients, structural changes in the intestinal
epithelium barrier allow LPS translocation into the bloodstream, resulting in increased plasmatic lev-
els of LPS, which in consequence, activates Toll-like receptor-4 (TLR4) leading to the production of
pro-inflammatory mediators, and sustaining low-grade systemic inflammation [72].
This condition known as metabolic endotoxemia induces a significant decrease in bacterial pop-
ulations which are crucial producers of beneficial gut-derived metabolites such as SCFA, thus sup-
porting the impairment of glucose metabolism and insulin resistance [73,74].
In addition, different studies have demonstrated that specific gut microbiota dysbiosis in mice
model of T2DM, induces GLP‐1 resistance and consequently, the impairment of GLP1-induced insu-
lin secretion which is crucial in the acquisition of the insulin resistance condition in diabetic individ-
uals [75].
At present, polyphenols have emerged as novel compounds that could interact with microbiota
and exert strong regulatory effects on intestinal bacteria, with subsequent regulation of gut microbi-
ota and its derivate metabolites [76]. These interactions between polyphenols and gut microbiota can
positively affect crucial metabolic markers of T2DM, improving systemic inflammation and insulin
sensitivity [77,78].
Growing evidence reveals that distinct types of polyphenolic compounds, such as genistein, cur-
cumin, and grifolic acid can increase GLP-1 secretion from L-cells via different mechanisms [79-82].
Besides their effect to directly stimulate GLP-1 secretion, some polyphenols, particularly luteolin,
apigenin, and resveratrol may also naturally suppress DPP-IV activity, which potentially increases
the half-life of GLP-1, thus stimulating glucose-dependent insulin secretion and regulating glycemia
[83].
Different studies demonstrate that different doses of oral intake of polyphenols including cate-
chins, and (-)-epigallocatechin-3-gallate (EGCG), can also favor the increase of different microbial
populations of SCFA-producing agents in fecal samples of human patients, thus improving the insu-
lin sensitivity and glucose homeostasis of individuals [84,85].
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In addition, other phenolic compounds including chlorogenic and ferulic acid can also act as
antidiabetic agents, through significant upregulating of the expression of GLUT4 and PPAR-γ, thus
favoring the uptake of 2-deoxyglucose (2DG) in time- and dose-dependent manner, and improving
the pathogenesis of T2DM progression [86-88].
Another feature of diabetogenic and overfeeding individuals is the increased expression of
branched-chain amino acids (BCAA) and BCAA-related metabolites such as the branched-chain keto
acids (BCKA) from the gut microbiome [89], which are well established as among the strongest bi-
omarkers of obesity, and insulin resistance, in consequence, potentiating the development of T2DM
[90,91]. Conversely, experimental results have demonstrated that lowering BCAA and BCKA levels
is associated with improved insulin sensitivity and reduced fat accumulation in mouse models [92].
Emerging studies have suggested that polyphenol administration may accelerate the catabolism
of BCAA, inducing a lowering of circulating BCAA levels, thus improving glucose homeostasis and
insulin sensitivity [93].
Additionally, some evidence also supports that intestinal catabolites of polyphenolic com-
pounds by the action of the gut microbiota could act as a strong antiglycative agent [94,95]. In this
sense, dietary polyphenolic intake may have a significant positive impact on the generation of gly-
cation products and diabetes-related complications [96,97].
Taken together, those findings suggest that a polyphenols-enriched diet can strongly modulate
the dysbiotic changes induced by hyperglycemia, improving the regulation of metabolites that me-
diates glucose homeostasis and insulin sensitivity in T2DM patients.

6. Vascular complications
Vascular complications in T2DM are those long-term complications that affect the blood vessels
network, and are responsible for most of the morbidity, and required hospitalization in these patients.
The vascular complications of diabetes are classified as either microvascular (retinopathy, nephrop-
athy, and neuropathy) or macrovascular, which includes coronary artery, peripheral, and cerebral
vascular diseases [98-100]. At present, a large body of compelling pieces of evidence support that
oxidative stress has a key role in the pathogenesis of vascular complications in diabetes [101-103].
As a major regulator of vascular homeostasis, the vascular endothelial cells play crucial roles by
controlling vascular tone through a balance between vasodilation and vasoconstriction, fibrinolysis,
platelet adhesion and aggregation, leukocyte activation, adhesion, and transmigration, smooth mus-
cle cell proliferation, and modulating the growth of blood vessels [104,105].
The onset of an imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species
(ROS), and proinflammatory factors, as well as a reduced nitric oxide (NO) bioavailability, are crucial
elements in the onset of the systemic disorder known as endothelial dysfunction [106]. NO is pro-
duced in the endothelium by the endothelial nitric oxide synthase, a Ca2+-calmodulin-dependent
enzyme that can convert the L-arginine to NO plus citrulline. By activation of soluble guanylyl
cyclase and modulation of cation channels, nitric oxide promotes VSMC relaxation and thus regulates
vascular tone. Additionally, nitric oxide is a crucial mediator in controlling platelet activation and
aggregation [107].
When ROS bioavailability overtakes the antioxidant defenses due to the onset of oxidative stress,
superoxide (O2−) rapidly inactivates NO and forms peroxynitrite (ONOO−), It is known that perox‐
ynitrite inactivates prostacyclin synthase (PGIS) and thus favoring the deterioration of vascular
health due to the vasodilatory, growth-inhibiting, antithrombotic, and antiadhesive effects of prosta-
cyclin (PGI2). Additionally, peroxynitrite increases the release of prostaglandin H2 (PGH2) and
thromboxane A2, which are potent vasoconstrictors, prothrombotic, growth- and adhesion-promot-
ing agents [108-110].
A growing body of data supports the beneficial roles of polyphenols to protect against endothe-
lial dysfunction induced by oxidative stimuli [111-113]. Of note, some polyphenols, as reported for
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resveratrol and its derivatives show dual protecting activities, either by the expression of Nox4, a
ROS-generating enzyme highly expressed in the endothelium, and by enhancing the expression of
two crucial members of the antioxidant defense of the vascular wall, such as glutathione peroxidase
1 (GPx1) and superoxide dismutase 1 (SOD1) [114]. Moreover, polyphenols seem to have peroxy-
nitrite-scavenging activity [115].
Furthermore, different reports have demonstrated that some polyphenols such as resveratrol
and others derived from strawberry and grapes skin and seeds, can promote the phosphorylation of
eNOS at Ser1177 by PI3K/Akt pathway, which is essential for NO production [116-118]. In addition,
resveratrol is reported to increase both endothelial eNOS mRNA and protein levels [119-121]. This
effect seems to be associated with the effects of resveratrol on SIRT1 and FOXO factors [122].

7. Polyphenols and advanced glycation.

Advanced glycation is one of the major pathways involved in the onset and progression of
T2DM complications, particularly those associated with the cardiovascular system [123]. Since the
pioneering works of the Vlassara group [124,125], a huge and compelling body of evidence has
demonstrated the paramount importance of advanced glycation end-products in diabetes complica-
tions, due to the hyperglycemic condition [126,127].
The formation of advanced glycation end-products (AGEs) involves the reaction of reducing
sugars, such as glucose, with the terminal amino groups of proteins, nucleic acids, or phospholipids
to initially form unstable Schiff bases, which evolve towards the formation of more stable compounds
called Amadori products, which by a series of complex reaction yield the AGEs. Degradation of both
Schiff bases and Amadori products rise to highly reactive short-chain carbonyl compounds, called α-
dicarbonyls [128].
These highly reactive compounds can also be formed by hexose autoxidation, as well as by-
products of either the glycolytic or polyol pathways and from lipid oxidation. Dicarbolyls can then
react non-enzymatically with lysine or arginine residues to produce AGEs [129,130].
The AGEs exert their deleterious effects, either directly by cross-linking of proteins, thus dis-
rupting protein functioning and turn-over [131,132], or indirectly by binding to a signaling receptor
for AGE-modified proteins, known as the receptor of advanced glycation end-products (RAGE)
[133,134].
Noteworthy, oxidative stress is an important contributor to the formation of endogenous AGEs,
by leading to the increased formation of endogenous reactive aldehydes as glyoxal, methylglyoxal
(MG), and thus favoring the formation of AGEs [135]. Additionally, when AGEs activate RAGE,
NADPH oxidase is activated and thus increases ROS levels [136].
At present, compelling evidence derived from experimental and clinical data studies support
the role of different polyphenols as very active inhibitors of the deleterious effects of AGEs, through
several mechanisms [137,139].
By their antioxidant activities, polyphenols are potent antiglycation compounds and anti-
glycation activity strongly correlates with the free radical scavenging activity and antiglycation ac-
tivity [94], as reported catechins, proanthocyanidins, anthocyanin, stilbenoids, and flavonols
[139,140]. Additionally, polyphenols have other properties which are essential to reduce the for-
mation of AGEs, such as the chelation of transition metal, as reported for chlorogenic and caffeic acids
[141,142].
The capacity of trapping dicarbonyl compounds is another crucial activity reported for some
polyphenols considering that dicarbonyls are one of the main precursors of AGEs [129], epigallocat-
echin-3-gallate, resveratrol, catechin, and epicatechin as well as different procyanidins can efficiently
trap both glyoxal and methylglyoxal [137,143,144].
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Dicarbonyls are detoxified by the glyoxalase system a highly specific enzyme responsible for the
detoxification of dicarbonyl species [145]. Some polyphenols can even stimulate this detoxifying sys-
tem [146].
Finally, several reports have demonstrated that polyphenols can actively reduce the undesired
consequences of the activation of RAGE, either by interfering with receptor signaling as well as by
reducing its expression [147-149]

8. Lipid metabolism
T2DM has been widely associated with an increased risk for atherosclerotic cardiovascular dis-
ease which is closely related to raised plasmatic LDL levels with important oxidative changes, [150]
which support diabetic hyperlipidemia and accelerated atherosclerosis, increasing the risk of macro-
vascular complication and cardiovascular morbidity. Noteworthy, LDL is a highly sensitive molecule
to hyperglycemia-induced hyperglycemia damage and modification, making them highly patho-
genic and atherogenic [151,152].
Under hyperglycemic conditions, transition metals in the presence of oxygen catalyze the autox-
idation of glucose or lipid peroxidation [153].
In addition, excess ROS formation in T2DM patients fuels vascular inflammation, and mediates
oxidized low-density lipoprotein (OxLDL) formation, which is considered a hallmark feature of ath-
erosclerotic development due to the crucial induction of atherosclerotic plaque progression and de-
stabilization in T2DM patients [154-156].
Besides the different pathways that conflux in activate NADPH oxidase and subsequent ROS
production in T2DM patients, the increased expression of ox-LDL also stimulates NADPH oxidase,
thus contributing to increment ROS formation and oxidative stress in T2DM patients [157].
In addition, hyperglycemia-mediated mitochondrial ROS production can also promote the NF-
kB-mediated entry of monocytes in atherosclerotic lesions, fueling the inflammation and progression
of unstable plaques, and increasing the risk of macrovascular complication in T2DM patients [158],
thus, sustaining a vicious cycle that perpetuating ROS production and oxLDL formation, contributes
to the progression of atherosclerosis unstable plaques on DM patients.
In last years, polyphenols have been postulated to lower lipids through different mechanisms
that imply beneficial effects on cardiovascular diseases of T2DM patients [159]. Based on their anti-
oxidant effects, different studies have shown that many polyphenols including resveratrol, apigenin
as well as synthetic polyphenol-like molecules can inhibit NAPDH oxidase activity, thus decreasing
vascular oxidation and atherogenesis in nondiabetic apolipoprotein (apo) E–deficient mice [160], as
well as improve hyperlipidemia and atherosclerosis in diabetic individuals [161].
Resveratrol based on its antioxidant activities can impact lipid metabolism and is considered an
important protective compound against LDL oxidation and atherosclerosis progression [162,163].
In this sense, the free radical scavenging activity of resveratrol has been investigated, revealing that
this polyphenol compound can interact with free radicals to form relatively stable free radicals and
non-radicals, resulting in inhibition of lipid peroxidation by Fenton reaction products [162,164],
which may decrease the progression of accelerated atherosclerosis through inhibition of oxidation in
T2DM patients [165,166].
More recently, it was demonstrated that resveratrol can upregulate endothelial nitric oxide syn-
thase (eNOS) expression by increasing cAMP levels, and decreasing ox-LDL-induced oxidative stress
in human endothelial cells, leading to a significant improvement of endothelial dysfunction and ath-
erosclerosis in mice [167]. Similar results have been demonstrated for quercetin, an important flavo-
noid, which have been demonstrate protective effects in diabetic individuals through significantly
reversed dyslipidemia and hepatic steatosis in diabetic mice, including lowered liver cholesterol and
triglycerides contents [168,169].
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Taken together, these findings suggest that dietary polyphenols may be crucial in the regulation
of dysregulated lipid metabolism through the modulation of antioxidative mechanisms in T2DM pa-
tients.

9. Conclusion remarks and future directions.

A compelling body of evidence suggests that dietary polyphenols may represent an important
alternative to the management of DM as well as in many of its complications (See Figure 1). Most
of the pieces of evidence derived from animals and in vitro studies support these issues, and only for
some polyphenols, solid clinical shreds of evidence have been provided. However, much more re-
search is needed on some topics that may be crucial to explain the current controversial results in
some clinical studies. In this regard, a full understanding of the metabolisms and bioavailability, the
assessment of dietary intake by measuring urine or blood polyphenol metabolites, duration of expo-
sure, delivery systems that guarantee high stability, as well as more efforts to understand the struc-
ture-activity relationship of polyphenols, are crucial elements to be considered in the design and ex-
ecution of more double-blinded clinical trials.

Figure 1. Polyphenols have multifaceted actions to support their use in the management of DM2, due
to their effects on pancreatic islet β-cell functioning and promotion of insulin production and signal-
ing, protection against micro-and microvascular complications, protection against the progression of
T2DM-associated obesity, management of dyslipidemia and gut microbiome dysbiosis.

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