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Antioxidants 12 (1): 123 (2023)
Akpoveso, Oke-Oghene Philomena
Ubah, Emeka Emmanuel
Obasanmi, Gideon
The global prevalence of diabetes continues to increase partly due to rapid urbanization and an increase in the aging population. Consequently, this is associated with a parallel increase in the prevalence of diabetic vascular complications which significantly worsen the burden of diabetes. For these diabetic vascular complications, there is still an unmet need for safe and effective alternative/adjuvant therapeutic interventions. There is also an increasing urge for therapeutic options to come from natural products such as plants. Hyperglycemia-induced oxidative stress is central to the development of diabetes and diabetic complications. Furthermore, oxidative stress-induced inflammation and insulin resistance are central to endothelial damage and the progression of diabetic complications. Human and animal studies have shown that polyphenols could reduce oxidative stress, hyperglycemia, and prevent diabetic complications including diabetic retinopathy, diabetic nephropathy, and diabetic peripheral neuropathy. Part of the therapeutic effects of polyphenols is attributed to their modulatory effect on endogenous antioxidant systems. This review attempts to summarize the established effects of polyphenols on endogenous antioxidant systems from the literature. Moreover, potential therapeutic strategies for harnessing the potential benefits of polyphenols for diabetic vascular complications are also discussed.
Citation: Akpoveso, O.-O.P.; Ubah,E.E.; Obasanmi, G. AntioxidantPhytochemicals as Potential Therapyfor Diabetic Complications.Antioxidants 2023, 12, 123. https://doi.org/10.3390/antiox12010123Academic Editor: Paola VendittiReceived: 30 October 2022Revised: 10 December 2022Accepted: 21 December 2022Published: 4 January 2023Copyright: © 2023 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).antioxidantsReviewAntioxidant Phytochemicals as Potential Therapy forDiabetic ComplicationsOke-Oghene Philomena Akpoveso 1,*, Emeka Emmanuel Ubah 2 and Gideon Obasanmi 3,*1 School of Basic Sciences, All American Institute of Medical Sciences, Black River,Saint Elizabeth Parish JMDEH03, Jamaica2 Department of Biochemistry, Michael Okpara University of Agriculture, Umudike 440109, Nigeria3 Department of Ophthalmology and Visual Sciences, The University of British Columbia,Vancouver, BC V5Z 0A6, Canada* Correspondence: o.akpoveso@gmail.com (O.-O.P.A.); gobasanmi01@qub.ac.uk (G.O.)Abstract: The global prevalence of diabetes continues to increase partly due to rapid urbanizationand an increase in the aging population. Consequently, this is associated with a parallel increase inthe prevalence of diabetic vascular complications which significantly worsen the burden of diabetes.For these diabetic vascular complications, there is still an unmet need for safe and effective alter-native/adjuvant therapeutic interventions. There is also an increasing urge for therapeutic optionsto come from natural products such as plants. Hyperglycemia-induced oxidative stress is centralto the development of diabetes and diabetic complications. Furthermore, oxidative stress-inducedinflammation and insulin resistance are central to endothelial damage and the progression of diabeticcomplications. Human and animal studies have shown that polyphenols could reduce oxidativestress, hyperglycemia, and prevent diabetic complications including diabetic retinopathy, diabeticnephropathy, and diabetic peripheral neuropathy. Part of the therapeutic effects of polyphenols isattributed to their modulatory effect on endogenous antioxidant systems. This review attempts tosummarize the established effects of polyphenols on endogenous antioxidant systems from the litera-ture. Moreover, potential therapeutic strategies for harnessing the potential benefits of polyphenolsfor diabetic vascular complications are also discussed.Keywords: diabetic complications; phytochemicals; polyphenols; oxidative stress; diabetic nephropa-thy; diabetic neuropathy; diabetic retinopathy; antioxidants1. IntroductionThe change in nutrition habits due to rapid urbanization and an increase in the ageingpopulation have contributed to an increase in the global prevalence of diabetes [1,2]. Conse-quently, diabetes is now a growing health concern, as the population of adults (aged 20 to79) living with diabetes was estimated to increase from 463 to 536.6 million people between2019 and 2021. An increment of a further 46%, to an average of 783.2 million diabeticadults, has been estimated to occur up to 2045 [3]. The latter increased level is projectedto be significantly higher in middle-income countries compared to underdeveloped anddeveloped nations [3].Diabetes is the root cause of several macrovascular and microvascular complications.Macrovascular complications associated with diabetes include atherosclerosis and stroke;and microvascular complications include diabetic retinopathy, nephropathy, and neuropa-thy. Generally, diabetes vascular complications effectuate the majority of the burden ofdiabetes. The characteristics of diabetic complications may vary from context to context—inhigh-income countries, recent studies suggest a decline in hospitalization and death tollamong older people with severe diabetic complications in the last 30 years [2,4]. However,in low- and middle-income countries (LMIC) such as Brazil, Ghana, Columbia, and China,Antioxidants 2023, 12, 123. https://doi.org/10.3390/antiox12010123 https://www.mdpi.com/journal/antioxidantsAntioxidants 2023, 12, 123 2 of 30and also among young adults, an increase in the prevalence of severe diabetic complicationswas observed [2]. This trend in LMIC was associated with healthcare deficiencies [2].In this respect, especially of LMIC, a parallel buildup of diabetes vascular complica-tions is set to have huge economic implications for these countries and the patients livingwith diabetes in these regions [1,2]. For instance, in North America and Caribbean (NAC)region, the cost of care for diabetes-related health conditions was estimated to be USD 414.5billion. In contrast, South East Asian countries such as Cambodia, Myanmar which areLMIC, have double the population of diabetic patients compared to NAC regions and wereestimated to spend USD 10.1 billion in 2021 [3], and in 2016 the cost of diabetes care inAfrica was evaluated to be over USD 4 billion per annum [1]. Moreover, health expenditureincreases parallelly by diabetes complications [1]. Furthermore, as a result of the financialburden and physical disabilities associated with diabetic complications, they significantlyreduce the quality of life of those living with them [5]. In light of the growth of diabetes andthe associated socio-economic impact of diabetes complications, interventions targetingimproved therapy and lifestyle of diabetic patients are urgently needed.Phytochemicals are secondary chemical metabolites that occur naturally in fruits,vegetables, and herbs that are known to possess different structures and can promotehealth benefits in humans [6]. Phytochemicals are critical in plant growth, development,and protection, including protection from harmful insects and microorganisms as well asextreme temperature and ultraviolet light exposure [7].Phytochemicals are categorized principally based on their structures as alkaloids,flavonoids, carotenoids, phenolics, terpenoids, steroids, and essential oils [8–10]. Sev-eral phytochemicals are recognized as the bioactive components of commonly availablemedicines, examples including salicylates sourced from willow bark which is present inaspirin which is used as pain and fever relief [11,12], quinine found in cinchona bark andused to treat malaria [13]. The largest group of phytochemicals in plants are the polyphe-nols (e.g., flavanones, flavonoids) known for their free radical scavenging activity. Freeradical scavenging activity of flavonoids, for example, is dependent on the number andposition of hydroxyl groups on aromatic rings and a C ring with a double bond conjugatedwith a 4-oxo function, which confers on them their reducing capacity [14,15].While phytochemicals provide the surest and quickest pathway to the discovery anddevelopment of new drugs, they also have some drawbacks which continue to restrict theiroverall acceptability. Challenges include the lack of a standardized dosage regimen, thepreparation, drug–herb interactions, and low bioavailability, for example, clearance of oralcontraceptives is increased by co-ingestion with St John’s wort [16]. Therefore, researchinto ways to maximize phytochemicals for therapy is required.The purpose of the current review is to discuss the body of literature on diabeticmicro-and macrovascular complications with a focus on: (1) the roles of oxidative stress (2)the activation of endogenous antioxidant defenses by exogenous phytochemicals, and (3)the therapeutic potentials of phytochemicals as alternative/adjuvant options.2. Diabetic ComplicationsDue to the progressive nature of diabetes, it eventually leads to complications whichare mainly microvascular and macrovascular. These complications have intense conse-quences on the anatomy, structure, and function of several cells, tissues, and organs, andconsequently on the patient’s well-being status [17].2.1. Diabetic Retinopathy (DR)DR is the most common microvascular complication of diabetes that can affect theretinal metabolism, physiology, and microvasculature of the eyes, it is also determinedrecently as the prominent cause of blindness in the working population [18]. The impact ofDR on normal vision varies broadly depending on the stage of DR and the earliest stageof DR may be asymptomatic [19–22]. General symptoms of DR which usually developAntioxidants 2023, 12, 123 3 of 30gradually could include temporarily blurred vision, floaters, and flashes of light or blindspots in the field of vision, and gradual or sudden loss of vision [23,24].Generally, DR is classically categorized into two major classes: non-proliferative DR(NPDR) and proliferative DR (PDR). NPDR symptoms are defects of the retinal vascula-ture including hemorrhages such as dot hemorrhages and blot hemorrhages [25,26], hardexudation [26,27], cotton wool spots [25–28], microaneurysms [25–27], and vascular leak-age [27,28]. The major PDR hallmarks are related to pathological retinal angiogenesis whichinvolves the growth of new abnormal blood vessels from the pre-existing vascular network,and pathological retinal neovascularization which encompasses the development of newblood vessels by de novo formation (vasculogenesis) and angiogenesis [26,29–33]. Theprogression from NPDR to PDR is characterized by ischemia, hypoxia, and the increasedexpression of proangiogenic growth factors including vascular endothelial growth factor(VEGF), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), andangiopoietin-2 (Ang-2) which activate the growth of aberrant retina blood vessels whichcan protrude into the preretinal space [30,31,34].Apart from the clinical features already discussed, other hallmark pathological changesin DR include pericyte loss, microglial activation, modifications to macroglial functions(Müller cells and astrocytes), thickening of the basement membrane, retinal leukocyteadhesion, blood–retinal barrier (BRB) breakdown, leukostasis, capillary nonperfusion,and capillary endothelial cell injury and death [25–27]; and degeneration of retinal neu-rons [35,36].Prevailing recommended treatments for DR are laser pan-retinal photocoagulation(PRP) [37,38], vitreoretinal surgery [27], and anti-VEGF intravitreal injections [39,40]. Al-though the aforesaid treatments may slow down the progression of DR towards blindness,they are not effective in tackling every instance of the disease and have significant sideeffects [38,41–45]; therefore, it becomes imperative to find exigent alternatives or adjuvanttherapeutic options to prevent DR or slow down its progression towards blindness.2.2. Diabetic Peripheral Neuropathy (DPN)DPN is a microvascular diabetic complication that is characterized by peripheral nervedysfunction. DPN is a significant cause of morbidity in diabetic patients and about half ofall diabetic individuals suffer from this complication [46]. In the clinic, the manifestationsof DPN include painful neuropathic sensations and insensitivity, the latter significantlyincreases the risk of unintentional injuries, burns, and foot ulcers, which potentially leads tonon-traumatic amputation and a significant reduction in the health status of patients [47,48].Once DPN initiates, it would be irreversible, but progression can be slowed down [49].The Toronto Diabetic Neuropathy Expert group categorized DPN into three majorclasses: (I) possible DPN, wherein any of the following signs or symptoms may be present:symptoms–decreased sensation, positive neuropathic sensory symptoms (e.g., “asleepnumbness”, prickling or stabbing, burning or aching pain) that predominantly occur inthe toes, feet, or legs, signs—a symmetric decrease in distal sensation or unequivocallydecreased or absent ankle reflexes; (II) probable DPN, wherein two or more of the follow-ing signs and symptoms of neuropathy are present: neuropathic symptoms, decreaseddistal sensation, or unequivocally decreased or absent ankle reflexes; and (III) confirmedDPN, wherein nerve conduction is anomalous and a sign or symptom of neuropathy ispresent [47].DPN is currently managed by tight glycemic control focusing on reducing HbA1c,however, for many patients, it is challenging to accomplish glycemic control [48]. The painsymptoms of DPN are managed with pharmacological agents including anticonvulsants(e.g., pregabalin and gabapentin) as the first-line pain therapy, serotonin–norepinephrinereuptake inhibitors (e.g., duloxetine and venlafaxine), secondary amine tricyclic antide-pressants (e.g., nortriptyline and desipramine) and opioid agonists (e.g., oxycodone andmethadone) [48,49].Antioxidants 2023, 12, 123 4 of 302.3. Diabetic Nephropathy (DN)DN is another microvascular diabetic complication that is the global leading cause ofend-stage renal disease (ESRD) and dialysis, constituting about 40% of total patients whoneed renal replacement therapy [50,51]. The mortality rate is about 30 times higher in DNpatients compared with other diabetic patients without DN [52]. Glomerular basementmembrane (GBM) thickening, mesangial matrix expansion, proteinuria (classically man-ifested as albuminuria), the development of characteristic Kimmelstiel–Wilson nodules,and progressive regression in glomerular filtration rate (GFR) are characteristic features ofDN [53,54].DN is classically categorized into five stages based on urinary albumin excretion(UAE), GFR, and blood pressure (BP) [52,54]: (1) glomerular hyperfiltration wherein, GFRis normal “>90 mL/min/1.73 m2” or increased, UAE value is <30 mg/day and BP isnormotensive; (2) silent stage, wherein, GFR is normal. UAE rate is <30 mg/day and BPis ±hypertensive along with thickened basement membrane; (3) incipient nephropathywith GFR of <60 mL/min/1.73 m2, microalbuminuria (UAE of 30–300 mg/day; the earliestclinically detectable sign), and BP of ±hypertensive; (4) overt nephropathy, wherein, GFRis <30 mL/min/1.73 m2, macroalbuminuria (UAE of >300 mg/day) and hypertensiveBP are present; and ultimately, (5) ESRD, wherein, GFR value is <15 mL/min/1.73 m2,with conditions of hypertensive BP and macroalbuminuria in which usually dialysis ortransplantation is required [54].Currently, tight glycemic and BP control, and the inhibition of the renin–angiotensin-aldosterone system (RAAS) via angiotensin-converting enzyme inhibitors or angiotensinII receptor blockers are the central approaches of DN therapy [52,54]. However, thesemanagement approaches have limitations in preventing DN progression towards ESRD,hence, effective therapies are urgently needed [54].2.4. Diabetes-Induced Cardiovascular and Cerebrovascular DiseasesDiabetics are at a greater risk of both cardiovascular and cerebrovascular diseases in-cluding atherosclerosis, cardiomyopathy, and stroke, which significantly increase morbidityand mortality in these patients [55–58].Atherosclerosis is a macrovascular disease that is the primary cause of various heartdiseases and stroke; diabetes-induced atherosclerosis is a significant cause of morbidityamongst diabetics [56,59]. It manifests as intimal thickening, inflammation, and narrowingof arteries by the build-up of plaques [59]. The Insulin Resistance Atherosclerosis (IRAS)study [56] has shown that compared with non-diabetics, diabetics have an increased rate ofprogression of carotid atherosclerosis, with diabetics having twice the mean progression ofintimal-medial thickness in both the common carotid artery and the internal carotid artery.Diabetic cardiomyopathy is the diabetes-induced functional and structural change ofthe myocardium in the absence of other risk factors including hypertension, coronary arterydisease, and significant valvular disease [55]. The lack of specific standardized guidelinesgoverning both the diagnosis and treatment of diabetic cardiomyopathy makes a definitivediagnosis, and treatment problematic [60]. Clinical pathological changes include cardiacremodeling, diastolic dysfunction, myocardial fibrosis, cardiac stiffness, impaired calciumhandling, increased atrial filling, enlargement, and increased left ventricular end-diastolicpressure [55,61].Stroke (or cerebrovascular accident) emerges due to the combination of extracranialcarotid artery disease and intracranial vessel diseases [62]. The risk of stroke is increased by36% in diabetics compared with non-diabetics [63] and one-third of all stroke patients arediabetics [64]. There are two main forms of stroke that may feature in diabetes, ischemic andhemorrhagic stroke, with both having the potential of significantly increasing morbidityand mortality amongst diabetics [65]; and in the clinic, stroke is manifested as asymptomaticcarotid artery occlusion or cerebral small vessel disease to transitory ischemic attack [62].Strict glycemic and lipid control as well as management of hypertension are essentialfor managing both diabetes-induced cardiovascular and cerebrovascular diseases; fur-Antioxidants 2023, 12, 123 5 of 30thermore, pharmacological interventions for diabetes-induced cardiovascular diseasesincluding glucagon-like peptide 1 (GLP-1) receptor agonists, agonists of peroxisomeproliferator-activated receptor gamma-γ (PPAR-γ) (e.g., pioglitazone), and the pharma-cological inhibition of sodium-glucose cotransporter type 2 (SGLT2) and RAAS (e.g., byan angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker)have shown clinical benefits [60,66–68]. Pharmacological interventions that can preventstroke in diabetics include pioglitazone and anti-platelet drugs, such as, clopidogrel andaspirin; however, to reduce the combined risk of ischemic stroke, myocardial infarction orvascular death, clopidogrel may be more effective than aspirin [68–70]. Although thesepharmacological interventions are available, they are inadequate for most diabetics andnovel alternative adjuvant treatment options are needed.3. Implications of Oxidative Stress in Diabetic ComplicationsInsulin deficiency due to the destruction/deficiency of β-cells is the main triggerof hyperglycemia in type 1 diabetes. A combination of factors such as hormonal andautoimmune dysfunction and environmental factors are associated with the destruction ofβ-cells [71]. In type 2 diabetes, hyperglycemia occurs due to impaired glucose uptake inskeletal muscles, deranged hormonal regulation of glucose metabolism, and impaired β-cellsecretory function [72]. In essence, hyperglycemia due to β-cell dysfunction is common indiabetes. The progression of diabetes and the development of vascular complications stemfrom hyperglycemia-induced β-cell and vascular damage. This damage is known to beassociated with reactive oxygen and nitrogen species (e.g., superoxide ion and nitric oxide).Although various processes are implicated in the pathophysiology of diabetic retinopa-thy, five major metabolic pathways are prevalently accepted to significantly contributeto the pathophysiology of diabetic complications: formation and accumulation of AGEs(advanced glycation end-products), increased expression of the receptor for AGEs (RAGE)and its activating ligands, activation of protein kinase C isoforms (PKCs), increased fluxvia the hexosamine pathway, and increased polyol pathway flux [73–77].The accumulation of AGEs and their interaction with RAGE can influence the per-meability and self-regulation of vascular endothelial cells, inducing inflammation andreleasing various proangiogenic cytokines and growth factors [76,78]. In DR, AGE accumu-lation and RAGE activation mediate the death of retinal pericytes, endothelial dysfunction,BRB breakdown, activation of NF-κB, and the induction of VEGF [78,79]. In diabetic com-plications, hyperglycemia promotes the production of diacylglycerol (DAG), an importantco-factor of PKC-α, β, and δ isoforms [75,76,79]. PKC–DAG interactions are observed in theretina, glomerulus, heart, and aorta where they may promote the remodeling of the base-ment membrane and consequently promote vascular dysfunction in the aforementionedtissues [76,80–82].The hexosamine pathway functions as an alternative pathway to the normal glycolysispathway in the hyperglycemic milieu [77]. As a result, excessive uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end-product of this pathway, is produced which canform glycolipids, glycoproteins, and proteoglycans which increases the burden of oxidativestress and worsen diabetic complications in various organs including the eyes and theheart [78,83–85]. In hyperglycemic conditions, one way that the activation of the polyolpathway contributes to the pathophysiology of diabetic complications is via increasedaldose reductase (AR) activity which metabolizes excess intracellular glucose into sorbitolusing NADPH as a cofactor and producing NADH [77,78,86]. As sorbitol accumulateswithin cells, osmotic damage and oxidative stress increase, and eventually, sorbitol isoxidized to fructose by sorbitol dehydrogenase (SDH) [78,86]. In DR, the accumulationof sorbitol and fructose in the retina correlates with increased oxidative stress, neuronalapoptosis, and astrocytes and Müller cell abnormalities [86,87]. The suppression of thepolyol pathway has also been shown to impede the progression of experimental DPN, andclinical DPN, DN, and DR [88,89].Antioxidants 2023, 12, 123 6 of 30These pathways are major reactive oxygen species (ROS) pathways thereby key con-tributors to increased oxidative stress, a crucial phenomenon in the pathogenesis of diabeticcomplications [74]. Furthermore, these five pathways lead to elevated inflammation, inflam-matory mediators, angiogenesis, and vascular anomalies [73–75]. However, of importanceis the possibility that these pathways are not independent of themselves but likely stimulatepathological changes in diabetic complications via a complex interplay [75]. In fact, Brown-lee [75] has provided multiple lines of evidence that these five pathways are controlledby a unified upstream event—the overproduction of mitochondrial superoxide by themitochondrial electron transport chain.Hyperglycemia and Oxidative StressGlucose-dependent insulin secretion relies on calcium ion influx into β-cells. Thisvoltage-dependent calcium ion influx is triggered by an increased ATP:ADP ratio due torising glucose intracellular concentrations. In physiological conditions, the intracellularATP:ADP ratio increases transiently and returns back. However, hyperglycemic conditionscause an excessive reduction in free ADP concentrations and an increase in the productionof reducing equivalents (NADH and FADH2). This results in an increase in the availabilityof reducing equivalents and accelerated oxidative phosphorylation. Consequently, thereis an excess of mitochondrial reductants such as coenzyme Q due to the lack of sufficientADP for ATP formation. In this condition, the reduction in available oxygen occurs at afaster rate than ATP formation and ROS production ensues [90].Endogenous antioxidant systems such as thioredoxin, glutathione, peroxidases, andthe like (to be discussed in later sections) maintain ROS within optimal concentrations.However, in hyperglycemic conditions, antioxidant systems become dysfunctional andROS-dependent signaling pathways are activated [91]. Furthermore, ROS generation frommitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX)is implicated in insulin signaling. NOX1 is proposed to be upregulated in hyperglycemicconditions possibly due to increased diacyl glyceride-induced protein kinase C (PKC)levels. Consequently, excessive NOX activity causes uncoupling of endothelial nitric oxidesynthase (eNOS) and increased production of peroxynitrite and superoxide [92,93].ROS overproduction is associated with the activation of various pro-inflammatory andgrowth pathways. For example, ROS mitochondrial overproduction has been associatedwith reduced mammalian target of rapamycin (mTOR) activity. In chronic hyperglycemicconditions, reduced mTOR activity has been associated with 5′ adenosine monophosphate-activated protein kinase (AMPK) -induced increase in ROS production [94] and increasedexpression of thioredoxin-interacting protein [95]; all of which result in reduced β-cell dif-ferentiation and function [96]. Furthermore, increased ROS production has been associatedwith a reduction in protein kinase B (AKT)/mTOR activation leading to β-cell-inducedapoptosis [97].In the same vein, the AKT/mTOR pathway is associated with insulin signaling andactivation of this pathway has been associated with improved survival of cardiomyocytesin diabetes-related myocardial infarction [98]. However, insulin resistance is proposed to beinduced by mitochondrial ROS generation [99] and parallel inhibition of the phosphatidyli-nositol 3-kinase (PI3K)/AKT insulin signaling pathway [100]. Therefore, mitochondrialROS generation is implicated in insulin resistance [99] and cardiac hypertrophy via mTOR-dependent mechanisms in diabetic conditions [98,101]. Furthermore, inhibition of insulinreceptor substrate (IRS) via ROS inactivation of the PI3K/AKT pathway leads to inhibitionof both glucose transporter 4 (GLUT4) translocation and glucose reabsorption in the skeletalmuscles [99].In essence, during over-nutrition states, a shift in redox status is implicated in insulinresistance and this results in impaired response to insulin in the skeletal/cardiac muscleand hepatic tissues with the characteristic dysfunctional control of glucose uptake anduncontrolled gluconeogenesis. In line with this, it is proposed that ROS-induced insulinresistance plays a major role in endothelial damage [73,102] and cardiovascular diabeticAntioxidants 2023, 12, 123 7 of 30complications [73,93]. Overall, ROS modulation of insulin signaling and growth pathwayssuch as the AKT/PI3K and mTOR pathways contribute to the progression of diabetes andthe development of diabetic vascular complications.In addition, ROS contributes to the progression of diabetes and the development ofdiabetic vascular complications by eliciting inflammation. For instance, downregulationof the mTOR signaling pathway via AMPK-dependent mechanisms has been shown toprotect cardiomyocytes and skeletal muscles from inflammation [103,104]. Moreover, ROSis implicated in activation of redox-dependent NF-kB activation via PKC-dependent mech-anisms [92,105]; redox-dependent serine/threonine phosphorylation and activation of JUNamino-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK) pathways [105].ROS activation of pro-inflammatory pathways is implicated in β-cell dysfunction and apop-tosis; and endothelial damage. This ultimately causes the progression and development ofcardiovascular complications [106].4. Enzymatic Endogenous Antioxidants and Diabetic ComplicationsThe endogenous antioxidant system consists of non-enzymatic and enzymatic antiox-idants. Enzymatic antioxidants include superoxide dismutase (SOD) which can includemetalloproteins such as manganese, copper/zinc SOD (MnSOD, Cu/ZnSOD), catalase(CAT), heme-oxygenases (HO), paraoxonase-1 (PON1) and the thioredoxins and glutaredox-ins system which include: thioredoxin (TRx) and glutaredoxin (GRx), TRx reductase (TrxR),glutathione reductase (GR), glutathione (GSH), and NAD(P)H. Other Trx/Grx-dependentsystems include glutathione peroxidase (GPx) and thioredoxin peroxidase (TrxP) [107](Figure 1). These are the common antioxidant defense systems in the vascular wall tocounteract ROS generation [108]. Non-enzymatic endogenous antioxidants include albu-min, ceruloplasmin, and metal-binding proteins [109]. The transcription and expressionof endogenous antioxidants are regulated by the nuclear factor erythroid 2-related factor2/antioxidant response element (Nrf-2/ARE) system [110]. Generally, endogenous an-tioxidants diffuse reactive oxygen species, via redox reactions. In essence, mitochondrialenzymes such as MnSOD convert superoxide ion to hydroperoxide (Figure 1). Hydrogenperoxide in the presence of intracellular iron (Fe2+) forms hydroxyl ions (Figure 1) whichoxidize proteins and cell membranes which can lead to deranged cellular signaling andapoptosis. However, TRx/GRx systems as shown in Figure 1, reduce hydroxyl ions andhydrogen peroxide thereby maintaining cellular redox homeostasis and cell viability [111].The next paragraphs of this review will focus mostly on enzymatic endogenous antioxidantsystems and their implications in diabetic complications.4.1. Enzymatic Endogenous Systems Implicated in Diabetic RetinopathyAs mentioned earlier, oxidative stress due to a compromised antioxidant system(Figure 1) is central to the development of diabetic complications. In the retina, the forma-tion of glycosylated proteins leads to the generation of free radicals and causes oxidativetissue damage due to glutathione (GSH) depletion [112]. Moreover, reduced activity ofNrf-2 and a parallel reduction in MnSOD, GPx, CAT, and mitochondrial function are sug-gested to occur in the retina in diabetic conditions [113]. Animal studies have shown thatincreased SOD3 (an isoform of extracellular SOD) prevented retinal muller cell activationand pericyte dysfunction [114]. Furthermore, extracellular SOD, CAT, and GPx are re-duced in patients with DR; consequently, they are suggested to be potential biomarkers forDR [115,116]. Moreover, thioredoxin-interacting protein (TXNIP), an endogenous thiore-doxin (Trx) inhibitor, works by inhibiting Trx reducing capacity and promoting cellularoxidative stress [117]. TXNIP is upregulated in diabetes and plays an important role in thepathophysiology of DR [118]. Taken together, the regulation of endogenous antioxidantenzymes in the diabetic retina is important in the management of DR.Antioxidants 2023, 12, 123 8 of 30Antioxidants 2023, 12, x FOR PEER REVIEW 8 of 32 reduced in patients with DR; consequently, they are suggested to be potential biomarkers for DR [115,116]. Moreover, thioredoxin-interacting protein (TXNIP), an endogenous thi-oredoxin (Trx) inhibitor, works by inhibiting Trx reducing capacity and promoting cellu-lar oxidative stress [117]. TXNIP is upregulated in diabetes and plays an important role in the pathophysiology of DR [118]. Taken together, the regulation of endogenous antioxi-dant enzymes in the diabetic retina is important in the management of DR. Figure 1. Endogenous antioxidants reactions with reactive oxygen species. MnSOD reacts with su-peroxide ion (O2−) converting it to hydrogen peroxide (H2O2). H2O2 diffuses to the cytoplasm and is converted to hydroxyl ion (OH−) via Fenton reaction with Fe2+. OH− cellular damage is prevented by glutaredoxin/thioredoxin, peroxidases (GPx, GRx, TRx), glutathione (GSH), and catalase (not shown). GSH is regenerated by nicotinamide adenine dinucleotide (NADH). 4.2. Endogenous Antioxidants in Diabetic Nephropathy (DN) The development of DN is attributed mostly to oxidative stress (OS) [119]. Some in-tracellular components, including the endoplasmic reticulum, peroxisomes, and mito-chondria, as well as particular enzyme clusters, such as NADPH oxidases (NOX), are in-volved in the formation of ROS in kidney cells [120]. Increased ROS levels are caused by either increased production, a failure of antioxidant mechanisms, or a combination of the two [121]. OS causes inflammation, kidney scarring, and other pathophysiological changes, resulting in further glomerular filtration rate (GFR) decline and DN progression Figure 1. Endogenous antioxidants reactions with reactive oxygen species. MnSOD reacts withsuperoxide ion (O2−) converting it to hydrogen peroxide (H2O2). H2O2 diffuses to the cytoplasm andis converted to hydroxyl ion (OH−) via Fenton reaction with Fe2+. OH− cellular damage is preventedby glutaredoxin/thioredoxin, peroxidases (GPx, GRx, ), l t t i e (GS ), and cat l se (notshown). GSH is reg n rated by nicotinamide adeni e dinucleotide (NADH).4.2. Endogenous Antioxidants in Diabetic Nephropathy (DN)The development of DN is attributed mostly to oxidative stress (OS) [119]. Some intra-cellular components, including the endoplasmic reticulum, peroxisomes, and mitochondria,as well as particular enzyme clusters, such as NADPH oxidases (NOX), are involved in theformation of ROS in kidney cells [120]. Increased ROS levels are caused by either increasedproduction, a failure of antioxidant mechanisms, or a combination of the two [121]. OScauses inflammation, kidney scarring, and other pathophysiological changes, resultingin further glomerular filtration rate (GFR) decline and DN progression [122]. Podocytedamage, proteinuria, and tubulointerstitial fibrosis are also linked to OS [123]. Trx, CAT,cytochrome c oxidase, SOD, and GPx perform antioxidant defense in the kidney [124].SOD is the first line of enzymatic antioxidant defense in the kidney [125]. The find-ings of studies on SOD in diabetes-induced chronic kidney disease (CKD) patients arecontradictory and challenging to interpret. Some researchers discovered no significantdifference in SOD levels between CKD patients and controls [126]. Others discoveredlower SOD activity in hemodialysis and peritoneal dialysis patients when compared tocontrols [127]. However, in animal studies, SOD1-transgenic db/db mice and STZ-treatedSOD1-transgenic mice had lower albuminuria, transforming growth factor (TGF)-β1, andAntioxidants 2023, 12, 123 9 of 30collagen IV expression, as well as mesangial matrix expansion and lower oxidative stressmarkers than control diabetic mice [128]. SOD2 deficiency has been linked to worseningrenal dysfunction, tubulointerstitial fibrosis, inflammation, and apoptosis [129] while SOD3expression was significantly increased in the glomerulus and tubular area of db/db miceafter supplementation with recombinant human SOD3. Recombinant human SOD3 supple-ments improved diabetic nephropathy by preventing ROS and the phosphorylation of theERK pathway [130].Hong et al. [131] also reported on the benefit of targeting extracellular SOD as atreatment for type 2 DN through intrarenal AMPK-PGC-1α-Nrf2 and AMPK-FoxOs sig-naling. Extracellular SOD increased phosphorylation of AMPK, activation of peroxisomeproliferative-activated receptor γ coactivator 1α (PGC-1α), and dephosphorylation offorkhead box O transcription factor (FoxO)1 and FoxO3a. The protective effects were at-tributed to enhanced nuclear translocation of Nrf2 and subsequently increased expressionof NADPH dehydrogenase 1 and HO-1 [131].Furthermore, in STZ-treated diabetic mice and db/db mice, proximal tubule-specificoverexpression of CAT in DN reduced angiotensinogen, p53, and proapoptotic Bcl-2associated X-protein (BAX) gene expression and decreased renal ROS generation and tubu-lointerstitial fibrosis [132,133]. This suggests a role of CAT in DN. In addition, glomerularGPx expression was lower in diabetic rats than in the normal control rats, and plasma andurine GPx levels were significantly lower in patients with diabetic glomerulosclerosis thanin patients without glomerulosclerosis [134].Wang et al. [135] reported on the role of kidney GPx4 expression level in DN progres-sion. The GPx4 expression level was significantly lower in DN patients than in healthycontrols and was associated with disease severity and progression [135]. Similarly, micewith DN showed significant changes in ferroptosis-associated markers such as increasedexpression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and de-creased expression levels of GPx4 [136]. Hence, the endogenous antioxidant systems CAT,SOD, and GPx are implicated in DN, and their upregulation may provide some benefit toDN patients.4.3. Endogenous Antioxidants in Diabetic CardiomyopathyThe endogenous antioxidants present in the heart protect against ROS toxicity. Theyinclude antioxidant enzymes such as SOD, CAT, GPx, GST, and glucose-6-phosphatedehydrogenase. ROS, such as superoxide anion, hydroxyl radicals, and hydrogen peroxide,play a role in mediating oxidative reactions in the development of diabetic cardiovascularcomplications [137,138]. Indeed, increased levels of malondialdehyde, thiobarbituric acidreactive substances (TBARS), hydroxynonenal (HNE), 8-hydroxyguanosine, 8-hydroxy-2′-deoxyguanosine, and 8-iso-prostaglandin F2α are biomarkers of chronic oxidative stress indiabetic cardiomyopathy [139].Cardiomyocyte enlargement, myocardial interstitial and perivascular fibrosis, inflam-mation, apoptosis, and elevated markers of oxidative stress are the main pathologicalcharacteristics of diabetic cardiomyopathy [140]. Apoptosis has been found to be signif-icantly increased in the myocardium of diabetic subjects [141]. Overexpression of themitochondrial tetrameric mnSOD or catalase in the diabetic heart enhanced respiration,shielded cardiac mitochondria from oxidative damage, and restored bulk in diabetic mito-chondria [142].Overexpression of GPx resulted in an improvement in left ventricular diastolic func-tion, and a reduction in cardiomyocyte hypertrophy, interstitial fibrosis, and myocardialapoptosis in mice with streptozotocin-induced diabetes [143]. Diabetic mice failed to de-velop cardiomyopathy when GPx was overexpressed under the control of a housekeepinggene promoter [143]. Many natural and synthetic Nrf2 activators have been shown inanimal models to be effective in preventing diabetic cardiomyopathy [144]. In view ofthis, it can be inferred that an altered endogenous antioxidant system is implicated in theAntioxidants 2023, 12, 123 10 of 30pathophysiology of diabetic cardiomyopathy and its upregulation might prove beneficialin managing the disease.4.4. Endogenous Antioxidants in Cerebrovascular Diabetic ComplicationsThe maintenance of the brain against oxidative stress involves both enzymatic and non-enzymatic antioxidants [145]. In diabetic cerebrovascular disorders including stroke andcognitive impairment, ROS increases the susceptibility to neuronal damage and functionaldecline via brain oxidation [146].Endothelial dysfunction characterizes ischemic stroke with an increase in ROS andlower levels of endogenous antioxidants in humans [147,148]. Both stroke patients andanimal models of stroke with middle cerebral artery occlusion (MCAO) have been shownto exhibit increased protein and lipid oxidation [149]. Moreover, a considerable rise in mal-ondialdehyde (MDA) levels was observed in patients with acute ischemic stroke 24 h andseven days after stroke, together with a decline in the levels of antioxidant enzymes [150].Resveratrol improved endothelial dysfunction by reducing the release of cytokinesthat promote inflammation, such as TNF-α and IL-1 [151], lowering oxidative stress in asirtuin1-dependent way [152] and promoting endogenous antioxidant enzymes such asSOD, CAT, and GPx [153]. Green tea extract and epigallocatechin-3-gallate (EGCG) reducedlipid peroxidation, which was increased after MCAO [154]. Additional improvements inneurological scores, decreased apoptotic neuronal death, increased GSH levels, decreasedinfarct size, and enhanced Nrf2 expression were observed after EGCG treatment [155]similar to the findings of Alfieri et al. on the benefit of Nrf2 activation in stroke injury [156].Diabetes-induced cognitive impairment is characterized by deficits in intelligence,attention, psychomotor efficiency, information processing speed, cognitive flexibility, andvisual perception [157]. Resveratrol hindered cognitive impairment induced by type 2diabetes mellitus (T2DM) [157]. Resveratrol treatment prevented learning and memorydecline in T2DM mice when compared to control mice [136]. Resveratrol also preventedT2DM-induced hippocampal neuronal destruction and synaptic ultrastructural damageand increased the expression of Nrf2 and its downstream genes which were decreased inthe T2DM group compared to the control [136]. These findings were similar to the report ofHan et al. on the prevention of cognitive impairment through activation of the Sirt1/Nrf2signaling pathway in diabetic rats through antioxidative mechanisms [158].A weakened endogenous antioxidant system is seen in various diabetes-induced cere-bral complications including ischemic stroke and cognitive impairment, while upregulatingthe endogenous antioxidant system provided some benefits in experimental models.5. Effects of Antioxidant Phytochemicals on Endogenous Antioxidant Pathways5.1. Effects of Antioxidant Phytochemicals on Mitochondrial Uncoupling Protein 2 (UCP2) andMitochondrial Function in Diabetic ComplicationsMitochondrial ROS generation is central to oxidative stress induced by hyperglycemiaand contributes to the development and progression of diabetic complications. Excessivemitochondrial ROS generation is associated with an increase in mitochondrial membranepotential. In fact, a reduction in membrane potential by mitochondrial uncoupling protein2 (UCP2) is known to reduce ROS production and prevent cell apoptosis [159].Caffeic acid phenylethyl ester (CAPE), a polyphenol has been shown to protect retinalcells against tert-butyl hydroperoxide induced oxidative stress. CAPE is known to havea similar structure to the 4-hydroxy-2E-nonenal natural inducer of UCPs. However, inthis study [160], CAPE was observed to be less toxic than 4-hydroxy-2E-nonenal. It wasalso shown to effectively reduce mitochondrial membrane at lesser concentrations than4-hydroxy-2E-nonenal. This activity of CAPE was inhibited by UCP2 siRNA and inhibitorsof UCP2 without affecting mRNA levels of UCP although a minimum but significantincrease in ATP production was observed [160]. This implies that, CAPE is similar to theendogenous UCP inducer-4-hydroxy-2E-nonenal: as it also reduces ROS production byreducing mitochondrial membrane potential via induction of UCP (Figure 2). Albeit, it hasAntioxidants 2023, 12, 123 11 of 30minimum effect on cellular energy metabolism and cell viability compared to 4-hydroxy-2E-nonenal.Resveratrol is proposed to prevent arrhythmia in diabetic conditions by alterationof UCP2 levels [161]. The altered expression of UCP2 has been linked to peroxisomeproliferator-activated receptor gamma coactivator1-alpha (PCG-1α), a regulator of mito-chondrial biogenesis [162] which is known to both upregulate and indirectly downregulatethe expression of UCP2 as negative feedback response.Mitochondrial membrane potential is also regulated by the alteration of mitochondrialpermeability via the formation of mitochondrial permeability transition pore (mPTP). Thevoltage-dependent anion channels (VDAC) and adenine nucleotide translocator (ANT)form the major channels for the exchange of ATP, proteins, water, and ions across themitochondrial membrane. Opening or Closing of these channels is regulated by binding ofanti/pro-apoptotic proteins (i.e., Bcl-2 /Bax), cyclophilin D, outer membrane transporterprotein (18 kDa) (TSPO), hexokinase, and creatinine kinase [163]. Polyphenols are proposedto modulate mPTP by altering the interaction of these “regulatory” proteins with VDACand ANT; or by directly binding to ANT as extensively reviewed by Naoi et al. [163]. Forexample, resveratrol prevents mitochondria membrane potential collapse by preferentiallyincreasing the interaction of antiapoptotic protein Bcl-2 with VDAC in the outer membraneof the mitochondria. This causes inhibition of mPTP opening, preventing the release ofcytochrome c and inhibition of apoptosis [163]. This effect could be beneficial in conditionssuch as myocardial infarction, which is characterized by the accumulation of mitochondrialROS and cell death due to the opening of mPTP, leading to the collapse of mitochondrialmembrane potential, the disruption of ATP production and induction of necroptosis [164].Furthermore, anthocyanins (cyanidin-3-glucoside, delphinidin 3-O-glucoside, pelargoni-din 3-O-glucoside) are reported to prevent the uncoupling of mitochondria in ischemiccardiac tissue. Skemiene et al. [165] observed that anthocyanins act as a substrate for mito-chondria complex 1, reduce cytochrome c, and thereby preserve mitochondria function. Areduction in cytochrome c has been associated with the inhibition of caspase-dependentapoptosis and restoration of cardiac function in diabetic rats [166]. Taken together, polyphe-nols exert a beneficial effect against ROS-induced vascular damage by maintaining mito-chondrial membrane potential via UCP2 and mPTP regulation; improving mitochondrialbiogenesis, improving electron transport chain function; thereby preventing necroptosisand cell death [167,168].5.2. Effects of Antioxidant Phytochemicals on Glutathione Peroxidase 4 (GPx4) and Coenzyme Q(CoQ) in Diabetic Complications and FerroptosisFerroptosis is a programmed cell death that occurs due to iron-dependent lipid peroxi-dation eliciting necro-inflammatory processes [169]. Iron overload is associated with theprogression of diabetes [170] and diabetic complications [171], likely due to hyperglycemia-induced expression of iron transporters in the intestines [172]. Iron propagates the forma-tion of lipid peroxide and eventual cell death via the Fenton reaction, enzymatic autoxida-tion of polyunsaturated fatty acids, and lipoxygenase catalytic formation of arachidonoyl-(AA-)OOH-phosphatidylethanolamine/arachidonic acid [173].Furthermore, lipid peroxides break down into hydroxy fatty acids or reactive alde-hydes MDA [174]; the latter is a known marker of oxidative stress in type 2 diabeticpatients [175]. GPx4 and coenzyme Q (CoQ) are two major antioxidants associated withreducing lipid peroxidation of mitochondrial and cellular membranes leading to ferropto-sis [169,176].As mentioned earlier, anthocyanins and quercetin are known to display “CoQ1 like”activity by acting as a complex 1 substrate during oxidative phosphorylation [165]. Theymay also bind lipid peroxides, thereby stabilizing the mitochondrial membrane duringischemia [165]. In addition, kaempferol and apigenin have been shown to increase CoQbiosynthesis in kidney cells [177] and resveratrol and para-coumarate serve as precursorsfor CoQ synthesis in human cells [178]. Based on the study by Fernández-del-Río et al. [177],Antioxidants 2023, 12, 123 12 of 30it appears that flavonoid structure with a single hydroxyl group located on the C4′ in theB ring together with a pie bond between the A and C ring is important for the significantsynthesis of CoQ. This is a common feature for resveratrol, kaempferol, and apigenin. Inaddition, the presence of these features and a hydroxyl group situated at C3 of the C ringelicits a much higher synthesis of CoQ10 as observed for kaempferol. Beyond CoQ synthesis,resveratrol was observed to increase mRNA expression of genes for CoQ synthesis andincrease CoQ10 levels in the liver of high-fat diet mice; however, the change in CoQ10 levelswas not significant [179].Furthermore, kaempferol is reported to reduce the risk of diabetic complicationsin diabetic rats by decreasing lipid peroxidation and increasing glutathione/glutathioneperoxidases in liver, kidney, and heart tissues [180], but the effect on CoQ levels is notreported. Polyphenols may contribute to CoQ levels and prevent lipid peroxidation andferroptosis. However, further studies are required.The role of GPx4 in ferroptosis and the implication for diabetic complications such asretinal damage; kidney damage, cardiomyopathy, and cognitive dysfunction is exemplifiedwith evidence reviewed by Yang and Yang [176]. In brief, GPx4 is dependent on GSHavailability for the reduction in lipid peroxides. GSH in turn is influenced by cysteinesynthesis and xc− transporter system, and NAD(P)H. The latter is affected by NOX activitywhich is implicated in cardiac injury [181] and diabetic cardiovascular diseases [182].Therefore, inhibiting NOX activity, upregulating GSH/GPx4 activity, and reducing ironoverload could be beneficial for preventing hyperglycemia-induced ferroptosis and relatedorgan damage [176].In line with the above, glabridin reduced genetic and protein expression of transferrinreceptor 1, while increasing genetic and protein expression of GSH/GPx4 and xc− trans-porter system. The study suggests that the reno-protective effect of glabridin was in partrelated to the reduction in iron load in the kidney and prevention of lipid peroxidation viaupregulation of the GSH/GPx4 system [183].Similarly, calycosin, an isoflavone, reduced markers for cellular labile iron pool andincreased GPx4 in kidney cells exposed to hyperglycemic conditions [184]. In the kidneysof diabetic mice model, calycosin was proposed to inhibit hyperglycemia-induced injuryby modulating ferroptosis [184]. In relation to diabetic cardiac diseases, naringenin wasobserved to reduce lipid peroxidation, and NOX2 expression in the cardiac tissue of diabeticmice, indicating potential ferroptosis mechanisms [185]. Moreover, astragaloside-IV is re-ported to reduce high-glucose-induced oxidative stress in retinal pigment epithelial cells byincreasing cysteine synthesis and GPx4 expression via Nrf2-dependent mechanisms [186].Prevention of vascular complications could also be attributed to the preservation ofB-cell function. Cryptochlorogenic acid, a major active component of mulberry leaf, andquercetin are known to prevent lipid peroxidation and consequent ferroptosis by upregu-lating GPx4 and reducing the accumulation of iron in pancreatic cells in animal diabeticmodels and in vitro studies [187,188]. Taken together, polyphenols prevent ferroptosisby modulating GSH synthesis, iron intracellular transport, and upregulating the GPx4antioxidant system (Figure 2), which could be beneficial for preventing the progression ofdiabetes and vascular complications.Antioxidants 2023, 12, 123 13 of 30Antioxidants 2023, 12, x FOR PEER REVIEW 19 of 32 Figure 2. Summary of the effects of polyphenols on endogenous antioxidant systems. In hypergly-cemia-induced oxidative stress, polyphenols increase UCP expression (1), reduces mitochondria membrane potential ΔΨm (2) which leads to reduction in O2− (3); preventing mitochondrial damage and apoptosis/necroptosis. Polyphenols enhance Gpx/GSH/Trx function by increase in synthesis of GSH via increased activity of Xc− transporter system, reduction in intracellular transport of Fe2+. Moreover, there is an increase in deacetylation activity of SIRT 3 which increases activity of isocitrate dehydrogenase activity (not shown) [189] and NADH leading to regeneration of GSH. Both the lat-ter and former prevent ferroptosis. Polyphenols also enhance SOD activity via SIRT1/3-dependent mechanisms. Finally, increased SIRT3 activity also increases translation of several antioxidant Figure 2. Summary of the effects of polyphenols on endogenous antioxidant systems. Inhyperglycemia-induced oxidative stress, polyphenols increase UCP expression (1), reduces mitochon-dria membran potential ∆Ψm (2) which l ads t reduction in O2− (3); preve ting mitochondrialdam ge and apoptosis/necro tosis. Polyph nols enhance Gpx/GSH/Trx functio by increase insynthesis of GSH via increased activity of Xc− transporter system, reduction in intracellular trans-port of Fe2+. Moreover, there is an increase in deacetylation activity of SIRT 3 which increasesactivity of isocitrate dehydrogenase activity (not shown) [189] and NADH leading to regenerationof GSH. Both the atter and former prevent ferroptosis. Polyphenols al o nhance SOD activityvia SIRT1/3-dependent mechanisms. Finally, increased SIRT3 activity also increases translation ofseveral antioxidant enzymes including NOQ1, HO-1, and CAT via Nrf2-dependent mechanisms.Activation of Nrf2 inhibits NF-kB transcription activity, thereby preventing oxidative stress-inducedinflammation which is associated with insulin resistance and endothelial damage.Antioxidants 2023, 12, 123 14 of 305.3. SIRTs and PolyphenolsSilent information regulator proteins (SIRTs) are regulator proteins that couple cellularnutrient sensing to intracellular redox homeostasis via NAD+-dependent mechanisms.SIRTs belong to the class III histone deacetylases and exist as SIRT 1-7 isoforms. SIRTsare localized in the cytoplasm, mitochondria, and nucleus. They are involved with theregulation of redox signaling, transcription of Nrf2 with the expression of antioxidantenzymes, and mitochondrial biogenesis [189,190]. The functions of SIRTs are extensivelyreviewed in Singh et al. [189].Resveratrol has been shown to activate SIRT1 activity thereby reducing oxidative stressand the progression of diabetes-induced kidney dysfunction in rats. SIRT1 activity reducedthe acetylation of FOXO3a, a key regulator of MnSOD expression [189,191]. Upregulation ofSIRT1 antioxidant activity by resveratrol is also associated with PGC-1α activation and thereduction in apoptosis with the improvement of mitochondria biogenesis [192]. Similarly,resveratrol is also shown to improve cardiomyopathy via the SIRT1/PGC-1α-dependentpathway [162]. Resveratrol is also reported to prevent mitochondrial membrane collapse bypreventing mPTP pore opening. The suggested mechanism was related to SIRT3-dependentinhibition of cyclophilin-D interaction with ANT [193].Furthermore, luteolin and fisetin were reported to increase the expression of SIRT1, 3,and 6 in human monocytic cells subjected to hyperglycemic conditions [194]. An increasein SIRT 1, 3, and 6 was associated with increased FOXO3a activity suggesting an effectof antioxidant enzymes [194]. In this respect, it can be said that resveratrol increasesthe activity of antioxidant systems (GSH, CAT, SOD) via SIRT1-dependent mechanisms.This implies that it could be useful for the prevention of diabetic kidney damage [195].Interestingly, resveratrol [196], luteolin, and fisetin [194] are also observed to reduce NOXactivity, suggesting the potential effect of preserving NADH for GSH antioxidant activityand related systems in the previous sections.In light of the above, it can be inferred that polyphenols activate SIRTs which inturn upregulate enzyme antioxidants (Figure 2). Polyphenol activation of SIRTs alsopreserves mitochondrial function and induces mitochondrial biogenesis. This effect mayalso contribute to the prevention of ferroptosis by preserving GSH/GPx antioxidant activity(Figure 2).5.4. Effects of Polyphenols on the Nuclear Factor (erythroid-derived 2)-like 2 (Nrf2) andEndogenous Antioxidant System5.4.1. Nrf2 RegulationThere are seven Nrf2 ECH homology domains (Neh 1-7) that regulate both the acti-vation and inhibition of Nrf2 activity [197]. Under normal conditions, Nrf2 is targeted byKelch-like ECH-associated protein 1 (KEAP-1) for cytosol degradation. KEAP-1 bindingto Nrf2 leads to ubiquitination by Cul3-Rbx1-E3 ligase. This negative regulator of Nrf2(KEAP-1) attaches to the amino-terminal of the Neh-2 domain containing DLG and ETGE asits binding motif through a double glycine repeat domain. Ubiquitination of Nrf2 leads toits proteasomal degradation. In essence, KEAP-1 inhibits Nrf2 transcriptional activity [198].Nrf2 stability is negatively controlled by the Neh-6 domain (Serine rich) which actsindependently of KEAP-1. DSGIS and DSAPGS, its conserved peptide motifs are recognizedby β-transducing repeat-containing protein (β-TrCP). Glycogen synthase kinase -3β (GSK-3β)-mediated phosphorylation of the DSGIS motif causes β-TrCP to bind more effectively toNeh-6 and promotes S-phase kinase 1 (SKP1)-cullin1 (Cul1)-F-box protein 1 (SCF) ubiquitinligase complex leading to Nrf2 proteasomal degradation [199]. Moreover, the Neh-7domain through binding with retinoid x receptor (RXRα) mediates repression of Nrf2transcriptional activity [200].Excess ROS causes redox disequilibrium and Nrf2 is translocated to the nucleus afterNrf2-KEAP-1 is disassembled. Once inside the nucleus, the Nrf2 Neh-5 domain functionsas a transcription factor and has a redox-sensitive nuclear export signal. Furthermore,the CNC-bZIP region on Neh-1 plays a crucial role in the binding of Nrf2 to DNA andAntioxidants 2023, 12, 123 15 of 30the small musculoaponeurotic fibrosarcoma (smaf) proteins [201] allowing Nrf2 to bindto antioxidant response elements (AREs: enhancer sequences in the regulatory region ofNrf2 target genes). This ultimately leads to activation and the expression of antioxidantgenes and iron genes involved in the stress response [110]. In addition, ubiquitination andphosphorylation of KEAP-1 by protein kinase C (PKC) phosphorylation also regulate Nrf2activity [202]. Other KEAP-1-independent regulation of Nrf2 includes the antagonism ofGSK-3β action by PI3k-/AKT signaling [197].Nrf2 activators including phytochemicals can upregulate Nrf2 activity to maximizeits antioxidant activity either through structural inhibition of KEAP-1, activation of theNfe2 (nuclear factor, erythroid 2) gene transcription, micro-RNA induced degradation ofKEAP-1, inhibition of proteasomal Nrf2 protein degradation and modulation of upstreamregulators of Nrf2. The following paragraphs will discuss examples of polyphenols thatactivate Nrf2 in select diabetic complications.5.4.2. Nrf2 in Diabetic CardiomyopathyNaringenin, a compound with known antioxidant and anti-inflammatory effects,has been investigated for its potential benefits in STZ-induced diabetic cardiomyopathy.Naringenin decreased blood sugar levels along with a reduction in myocardial fibrosisand cardiomyocyte death [185]. Naringenin also significantly increased the expressionof antioxidant enzymes and Nrf2, while inhibiting pro-inflammatory cytokines, reactiveoxygen species levels, and nuclear factor kappa-B (NF-kB) expression [185]. Naringeninmay control Nrf2 and NF-kB pathways to prevent diabetes-related cardiac damage bylowering oxidative stress and reducing inflammation [185].Furthermore, garlic oil (diallyl trisulfide) boosted Nrf2 protein stability and nucleartranslocation, protecting against hyperglycemia-induced ROS-mediated apoptosis by up-regulating PI3K/AKT/Nrf2 pathways [203], in cardiomyocytes exposed to high glucose.This suggests that garlic oil may improve insulin sensitivity in cardiac myocytes via Nrf2-dependent mechanisms.5.4.3. Nrf2 in Diabetic NephropathyNrf2 is elevated in diabetic kidneys in both humans and animals in the early stagesof the disease while its capacity to translocate into the nucleus is decreased, indicatingfunctional impairment of Nrf2 [204]. Consequently, impaired NrF2 activity in DN leads tothe accumulation of peroxide radicals which harm kidney cells [205].EGCG reduced DN by activating the Nrf2/ARE signaling pathway by downregulatingKEAP-1 and disrupting the Nrf2-KEAP-1 interaction, thereby increasing nuclear Nrf2 [204].Sun et al., 2017 confirmed these findings by reporting that EGCG increased Nrf2 expres-sion to prevent diabetic nephropathy [206]. A 24-week EGCG treatment activated Nrf2expression and function in wild-type mice without affecting KEAP-1 expression. Diabetes-induced renal oxidative damage, inflammation, fibrosis, and albuminuria were all reversedby Nrf2 activation, while deletion of the Nrf2 gene negated the effects of EGCG [206]. Takentogether, the data suggest that EGCG could activate Nrf2 via the KEAP-1-dependent andindependent pathway.Altamimi et al. [207] investigated the role of ellagic acid in the prevention of DN.Ellagic acid reduced NF-κβ, upregulated GSH, γGCL, and SOD, and increased nucleartranslocation of Nrf2 while preventing renal damage, oxidative stress, inflammation, andapoptosis. Ellagic acid also inhibited KEAP-1 cytoplasmic expression and interaction withNrf2, as well as increased AKT and GS3KB phosphorylation [207].Sinapic acid, a polyphenolic metabolite, was found to have antioxidant and anti-inflammatory properties in DN by upregulating the Nrf2/HO-1 signaling pathway [208].A similar effect has also been observed for astaxanthin in diabetic rats. In addition to upreg-ulating the Nrf2/HO-1 signaling pathway, astaxanthin also increased SOD-1 and reducedfibronectin and collagen IV accumulation in the kidneys of diabetic rats. Astaxanthin alsoreduced MDA levels suggesting a reduction in oxidative stress in diabetic rats [209].Antioxidants 2023, 12, 123 16 of 30Paeonol (PA), a phenolic compound derived from the cortex mountain root bark, wastested for antioxidant activity in glomerular mesangial cells and STZ diabetic mice byZhang et al. [210]. PA provided renoprotection by activating the Nrf2/ARE pathways viaSIRT1, suggesting that PA slows the progression of diabetic renal fibrosis [210].Hesperitin is also reported to provide renoprotection against DN by upregulatingthe Nrf2/ARE/glyoxylase pathway and augmenting γGCL, a target gene of Nrf2/AREsignaling [211].These evidences suggest that polyphenols activate the endogenous antioxidant sys-tems in DN via upregulation of Nrf2 activity by inhibiting its proteasomal degradation andimproving its translocation to the nucleus and could provide an additional option in thepharmacotherapy of diabetic complications including DN.5.4.4. Nrf2 in Diabetic RetinopathyShi et al. [212] investigated the effects of rhaponticin, a polyphenol stilbene, in DR ofdiabetic rats. Rhaponticin caused upregulation of Nrf2, NQO-1, and HO-1, while MDA lev-els were significantly reduced, along with increased activity of SOD, CAT, and GPx. Othereffects of rhaponticin include the downregulation of TNF-α, matrix metalloproteinase-2,and the upregulation of IL-10 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in theretina. These findings demonstrate the importance of Nrf2 in maintaining redox homeosta-sis in the retina, as well as the ability of rhaponticin to prevent diabetic retinal changes viaantioxidant, anti-inflammatory, and hypoglycemic effects [212].Curcumin, a natural polyphenol significantly reduced retinal edema and outperformedinsulin in terms of anti-photoreceptor apoptosis [213]. Curcumin alleviated compensatoryNrf2 pathway activation by directly reducing free radicals when combined with insulin,and it better maintained Nrf2 pathway homeostasis compared to insulin alone in theearly stages of diabetes [213]. When combined with hypoglycemic agents, curcumin wasbeneficial in the management of diabetic complications [213]. Bucolo et al. also reporteda similar effect of curcumin in high glucose-induced DR [214]. Antioxidant activity waslinked to the activation of the Nrf2/HO-1 pathway through the ERK pathway [214]. Thissuggests antioxidant and anti-inflammatory effects of curcumin in DR.Blueberry anthocyanin extract (BAE) protected human retinal capillary endothelialcells from high glucose injury [215]. BAE increased the levels of Nrf2 and HO-1 mRNAwhile decreasing vascular endothelial growth factor (VEGF) and increasing antioxidantenzymes such as GSH and GPx. The antioxidant effect was achieved by activating theNrf2/HO-1 pathways [215]. A comparison of BAE and the anthocyanin constituents (mal-vidin, and malvidin glucosides) showed that malvidin-3-glucoside was the most effectivefor inhibiting high glucose-induced ROS production in human retinal capillary endothelialcells (HRCECs). Moreover, malvidin-3-glucoside did not inhibit NOX4 expression butincreased CAT and SOD expression. Furthermore, BAE, malvidin, and glucosides inhibitedVEGF, ICAM, and NF-κB expression [216]. Malvidin-3-glucoside and other anthocyaninsin grape pomace were suggested to modify KEAP1/Nrf2 interaction and increase theexpression of HO-1 and NQO1 antioxidants [217]. This suggests that malvidin-3-glucosideand the likes inhibit inflammation in endothelial cells by improving antioxidant enzymaticexpression via Nrf2 signaling-dependent mechanisms.Pterostilbene, a natural stilbene with documented antioxidant activity has shownprotective activities against DR [218]. Pterostilbene conferred protection by reducingprotein and lipid oxidative damage and restoring antioxidant enzyme activities, which itaccomplished by activating the PI3K/Akt/GSK3/Nrf2 pathways [218]. Matos et al. [219]extensively reviewed the benefits of flavonoids in DR [219].In summary, polyphenols can confer protection against oxidative stress via upregu-lating endogenous antioxidants through the Nrf2/KEAP-1 pathway in DR and could bepharmacologically targeted in the future management of DR.Antioxidants 2023, 12, 123 17 of 305.4.5. Nrf2 in Diabetic Peripheral NeuropathyDPN pathogenesis is influenced by oxidative stress and neuroinflammation [220].Phytochemicals have also been studied as Nrf2 activators in the management of DPN.Fisetin, a phytoflavonoid, has been shown in experimental DPN to protect from oxidativestress and neuroinflammation via NF-κB inhibition and Nrf2 upregulation [221]. Nrf2increased the levels of antioxidant enzymes such as HO-1, NQO-1, and GCL [221].Morin, a bioflavonoid with documented antioxidant capacity has been investigated forits benefits in experimental DPN [222]. Morin reduced high glucose-induced mitochondrialsuperoxide production, membrane depolarization, and ROS generation while increasingNrf2 activity and inhibiting Nf-KB-mediated neuro-inflammation [222]. Rutin was alsobeneficial in the STZ model of DPN. When compared to DPN control rats, rutin combinedwith the cyclooxygenase 2 (COX-2) inhibitor nimesulide reversed oxidative damage asevidenced by increased levels of SOD, CAT, and GSH, as well as Nrf2/HO-1 activation inthe sciatic nerve [223].Overall, Nrf2 regulates the expression of several antioxidant enzymes and can be saidto be central to increased endogenous antioxidant activity. Moreso, polyphenol antioxidantactivity via modulation of Nrf2 signaling inhibits hyperglycemia-induced inflammationand apoptosis (Figure 2). This emphasizes the benefits of polyphenols for targeting the Nrf2signaling pathway in the management of diabetic complications. Table 1 below highlightsexamples of polyphenols and their effect on antioxidants for the benefit of various diabeticcomplications.Table 1. Summary of examples of polyphenols and their effects on endogenous antioxidant systemsin diabetic conditions.Antioxidant System Examples of Polyphenol EffectsUCP2/mitochondrial Complex 1 Caffeic acidAnthocyaninsIn vitro protection of retinal cells, improvingmitochondrial function [160].Improve cardiac function by preservingmitochondrial function in diabetic rat model [166].SIRTs ResveratrolImprove GSH, CAT SOD activity andmitochondria function via activation ofSIRT1/PGC-1α/FOXO3a.GSH/GPx4/Xc− system(Inhibition of ferroptosis)Glabridin and calycosin Reno-protective effect in DN rat model [183,184].Naringenin Cardio protective effect [185].Astragaloside-IV In vitro protection of retinal cells [186].Quercetin and cryptochlorogenic acid Preserving β-cell function [87,188].Nrf-2 Epigallocatechin-3-gallateCurcuminReno-protective effect in DN [206].Protective effective against retinal injury indiabetes [213].5.4.6. Polyphenol and Endogenous Antioxidants EffectFrom the previous sections, the polyphenol effect on SIRT1/3 activity can be consid-ered a signaling connector between ROS production, GPx function, and Nrf2 signaling.This is because they activate MnSOD, increase NADH which is crucial for GPx functionand increase Nrf2 signaling. The latter then leads to the upregulation of other antioxidantsand anti-inflammatory effects (Figure 2). Moreover, ROS overproduction is associatedwith insulin resistance [99,103], and polyphenol upregulation of endogenous antioxidantsvia Nrf2-dependent mechanisms can be said to be beneficial for insulin resistance by theupregulation of the PI3K/AKT pathway [218]. Polyphenol modulation of mTOR via thePI3K/AKT pathway could be beneficial for the prevention of cardiac hypertrophy andpreserving β-cell function [97,98,101]. Therefore, targeting the Nrf2 pathway and theSIRTs could be beneficial for the prevention of insulin resistance and associated diabeticAntioxidants 2023, 12, 123 18 of 30cardiovascular complications. Regulation of the Nrf2 pathway by microRNAs has beenstudied. microRNAs could also be modulated by polyphenols and can indirectly modulateantioxidant activity [224].Other antioxidants such as paraoxonase are modulated by polyphenols. Glabridin,at levels lower than antioxidant concentrations, was shown to increase expression andtranscription of PON2, in addition to MnSOD and CAT in hyperglycemic mice. The mecha-nism of action was suggested to be via protein binding with PON2 [225]. A similar studywith curcumin-enriched yoghurts and metformin in diabetic rats showed that curcuminsustained the function of PON1 in diabetic conditions probably via preventing glycationof PON1 [226]. Taken together, glabridin and curcumin could prevent atherosclerosis byupregulating PON activity and reducing lipid peroxidation [225,226].Glabridin was also shown to inhibit lipopolysaccharide-induced inflammation inTHP-1 cells by downregulating the expression of inducible nitric oxide synthase (iNOS).Downregulation of iNOS and nitrotyrosine production was also observed in the liver ofhigh-fat-fed mice. This suggests that glabridin could prevent inflammation associated withnutritional-induced oxidative stress (i.e., hyperglycemia) [227].In relation to inflammation, polyphenols such as punicalagin, prevented nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein3 (NLRP3) induced pyroptosis (inflammation-induced cell death) by inhibiting NOX4activity. This in turn reduces Trx-TXNIP dissociation and subsequent activation of NLRP3.The data suggest the role of polyphenol modulation of the Trx antioxidant system forpyroptosis in the development of DN [228].Polyphenols could also indirectly exert antioxidant activity through highly lipophilicgut microbial-derived metabolites [229]. Therefore, polyphenol gut microbiota interac-tions contribute to systemic polyphenol antioxidant activity. Iatcu et al. [230] extensivelyreviewed the role of gut microbiota in various type-2 diabetes complications. In general,the proportion of Bifidobacterium spp. and Lactobacillus spp. to Enterococcus spp. andClostridium spp. is reduced in patients with type 2 diabetes and complications.Gallic acid is known to modulate gut microbiota in different conditions includingstress and inflammatory bowel disease [231]. An evaluation of healthy dog fecal contentrevealed that long-term supplementation of gallic acid increased anti-inflammatory short-chain fatty acid concentrations. This increase was positively correlated with an increasein Erysipelotrichaceae_unclassified spp. and Faecalibacterium spp., and a decrease in theproliferation of pro-inflammatory Parasutterella spp.; suggesting a beneficial prebiotic andanti-inflammatory effect of gallic acid. In this study, gallic acid supplementation was alsoassociated with increased levels of CAT and SOD [231].In a similar study, olive oil enriched with polyphenols and thyme elicited an increasein Bifidobacterium spp. in humans. Furthermore, a reduction in Clostridium spp. wasassociated with a decrease in isolithocholic acid; the latter is associated with a reducedrisk of cardiometabolic disease in chronic insomnia [232]. Furthermore, the prebiotic effectof olive oil enriched with polyphenols was associated with reduced oxidized low-densitylipoproteins and increased microbial metabolites of procatechuric and hydroxytyrosol,suggesting a relationship of gut-derived metabolites and antioxidant activity [233].In fact, specific gut microbiota-derived polyphenolic metabolites also retain the abilityto modulate antioxidant systems. For example, in vitro studies on urolithins A and B (gutmicrobial metabolites derived from polyphenols) are known to preserve podocyte functionby upregulation of Bcl-2 expression and nephrin expression. Urolithin A, specifically, up-regulated Bcl-2 in high glucose conditions [229]. In vivo studies with urolithin A have beenshown to prevent renal kidney injury in vivo via the Nrf2 signaling pathway [234]. Theseresults suggest that polyphenols–gut microbiota interactions contribute to the modulatoryeffect of polyphenols on endogenous antioxidants.Overall, polyphenols influence endogenous antioxidant systems via multiple mecha-nisms. A summary of the effects of polyphenols on some endogenous antioxidant systemsis represented in Figure 2 below.Antioxidants 2023, 12, 123 19 of 306. Potential Therapeutic Strategies to Alleviate Diabetic Complications via theActivation of Endogenous Antioxidants by Exogenous Antioxidant PhytochemicalsOne therapeutic strategy for harnessing the beneficial effects of polyphenols couldbe drug synthesis. For example, redesigning polyphenols to include imidazole deriva-tives [235,236] might prove a potential way to harness polyphenols for insulin resistancevia Nrf2-dependent mechanisms. Structure-related activity of studies could assist withthe identification of phenolic components with high affinity for inducing antioxidant sys-tems. For instance, cyanidin is a potential drug candidate for antioxidant therapy as it wasidentified as a potent activator of SIRT6 [237]. Further drug discovery studies are requiredto harness this potential of cyanidin. For example, the chemical synthesis of cyanidinanalogs coupled with in silico studies could facilitate the discovery of cyanidin analogswith optimized pharmacokinetic properties and less toxicity [238]; making it useful fortherapy of diabetic complications. Taken together, further studies of chemically modifiedpolyphenols and their effect on antioxidant systems are required.Beyond synthetic drug designs, harnessing the health benefits of polyphenols in theirnatural form depends on their bioavailability. However, bioavailability is influenced byseveral factors such as food source, food processing, gut microbiome/hepatic biotransfor-mation, and individual variability. Rodriguez-Mateos et al. [239] reported the bioavailabilityof polyphenols after the consumption of berry drinks compared to berry bun in healthyvolunteers. Bioavailability and physiological effects on the endothelium were associatedwith heat processing and gut microbiome biotransformation—only the latter had an effectsix hours post-consumption and was associated with unprocessed berry drink [239]. Withrespect to studies by Rodriguez-Mateos et al. [239], cooking may also improve the availabil-ity of polyphenols as reported in the study by Abukhabt et al. [240]. Heat processing causesa release of polyphenols from the food matrix and can increase absorption and colonicconcentrations both of which are crucial for polyphenol bioactivity.As discussed earlier, it is accepted knowledge that the gut microbiome is implicatedin the therapeutic benefits of polyphenols. Gut microbiome dysbiosis is implicated inthe disruption of intestinal tight junctions, a common pathological feature of aging anddiabetes. Hidalgo-Liberona et al. [241] suggest that decreased intestinal integrity mayreduce the bioavailability of gut microbiome-derived polyphenolic metabolites but increasethe bioavailability of phase II metabolites. The implication of this could mean that whenpatients with compromised intestinal integrity (e.g., diabetic patients) consume flavonoid-rich metabolites, for instance, there may be increased anti-inflammatory activity of theflavonoids in these patients when compared to consuming the intact polyphenol due toincreased bioavailability of phase II metabolites as reviewed in Williams et al. [242]. Fur-thermore, genetic polymorphisms of phase II enzymes may influence the bioavailability ofpolyphenols as reviewed in Manach et al. [243]. Therefore, in the future, understanding ge-netic polymorphisms and their effect on phase II polyphenolic metabolites would be usefulfor reducing variability to polyphenol therapy and improving the efficacy of polyphenolsfor the management of diabetic complications.Moreover, given that gut microbiome-transformed metabolites were associated with abeneficial effect on the endothelium long after consumption [239]; it can be recommendedthat polyphenol benefits in diabetic patients may need to be enhanced with probiotics [244]for the prevention of endothelial damage, which is central to diabetic complications.In addition, recent evidence suggests that the production of gut microbiome-derivedmetabolites from polyphenols could differ within individuals. Iglesias-Aguirre et al. [245]observed that resveratrol is metabolized to lunularin by mostly male compared to femaleindividuals. According to Cortés-Martín et al. [246], such variations should be regarded asmarkers for human polyphenol-related metabotypes. However, given the evidence on theimpact of equol metabotype/equol gut microbiota metabolizing ability on cardiometabolicrisk factors as reviewed in Frankenfield [247], consideration of human polyphenol-relatedmetabotypes might be important to identify specific metabotypes to maximize the benefitsof polyphenols. This is promising for precision medicine. Besides, pharmacological therapyAntioxidants 2023, 12, 123 20 of 30for metabolic syndrome could also have a beneficial influence on prebiotic effect of polyphe-nols, depending on cardiovascular risk factors and the associated medications [248]. Takentogether, further research into individual variations due to sex, race, polyphenol-relatedmetabotypes, and pharmacotherapy presents the opportunity for understanding how fa-vorable drug–polyphenol–gut microbial interactions can be harnessed for the therapy ofdiabetes and diabetic complications.Finally, the use of various nanoparticle platforms and encapsulation in food has beenshown to improve the efficacy of polyphenols by increasing systemic and local delivery ofpolyphenols as extensively reviewed in [249,250]. It will be important to consider stability,especially in food particles, and the risk that metal-based and lipid-based nanoparticles maycause oxidative stress. Therefore, the design of polyphenol-based nanoparticles should takeinto consideration the route and could include a combination of polyphenols to mitigateany potential toxicity due to oxidative stress [251,252]. Further clinical including toxicitystudies are required to validate the use of nano-based polyphenols in the management ofdiabetic complications.7. ConclusionsThe development and progression of diabetic complications are associated with vari-ous oxidative stress and inflammatory pathways. Various phytochemicals possess antioxi-dant, anti-inflammatory, and anti-hyperglycemic properties which can potentially preventor impede the progression of diabetic complications. However, the low bioavailabilityand absorption of antioxidant phytochemicals currently limit their utility in the clinic.Further studies are needed to further explore the antidiabetic potentials of phytochemicals,improve their absorption and bioavailability, and explore their potential side effects inclinical trials. A future in which more diabetic patients will rely on phytochemicals as analternative/adjuvant therapy for preventing or treating diabetic complications is one inwhich bioavailability is improved, and dosage standardization has been achieved eitherfor the crude extracts or the purified bioactive compounds. The hope is that in combina-tion with currently available treatment approaches, antioxidant phytochemicals wouldsignificantly reduce the burden of diabetic complications.Author Contributions: Conceptualization, G.O. and O.-O.P.A.; investigation, O.-O.P.A., E.E.U. andG.O.; writing—original draft preparation, O.-O.P.A., E.E.U. and G.O.; writing—review and editing,O.-O.P.A. and G.O.; visualization, O.-O.P.A. and G.O.; supervision, G.O.; project administration, G.O.All authors have read and agreed to the published version of the manuscript.Funding: This research received no external funding.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: Data is contained within the article.Conflicts of Interest: The authors declare no conflict of interest.References1. Misra, A.; Gopalan, H.; Jayawardena, R.; Hills, A.P.; Soares, M.; Reza-Albarrán, A.A.; Ramaiya, K.L. Diabetes in DevelopingCountries. J. 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Multidisciplinary Digital Publishing Institute
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diabetic complications
phytochemicals
polyphenols
oxidative stress
diabetic nephropathy
diabetic neuropathy
diabetic retinopathy
antioxidants
Antioxidant Phytochemicals as Potential Therapy for Diabetic Complications
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