Role of antioxidants as immunity booster in obesity and diabetes: a systematic review on neuro-gliopathies perspective

Background: The main objective of the study was to carry out a systematic literature review to investigate the beneficial role of antioxidants in obesity and diabetes and the association of antioxidants in neuro-gliopathies and gut microbiome on antioxidant production and enteric nervous system (ENS) protection. Methods: A literature search was done electronically on 8 June 2022 in the databases Google Scholar


Introduction
Antioxidants are the chemical compounds present endogenously as a normal defense mechanism of the host cell or can be taken from the diet.Some examples of enzymatic antioxidants include superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione S-transferase (GST) and the nonenzymatic antioxidants like reduced glutathione (GSH), carotenoids, flavonoids, lipoic acids, and vitamin A, C and E. GST converts reactive electrophilic species to hydrophilic forms and easily excretable products as a result of their conjugation with GSH.Vitamin C and E are involved in the termination of the lipid peroxidation process.The flavonoids help in scavenging free radicals, and some proteins act as antioxidants such as peroxiredoxin, thioredoxin (TXN), and glutaredoxins [1].Emerging studies reports indicate that natural antioxidants can modulate oxidative stress (OS) and improve immune function in obesity and diabetes [2].So, the supplementation of lipoic acid, zinc, carnitine, cinnamon, green tea, and the vitamins C and E, and some evidence for omega-3 polyunsaturated fatty acids, coenzyme Q10 (CoQ10), green coffee, resveratrol, or lycopene [3].
Current findings indicate that inadequate serum levels of a few antioxidants may be associated with excess fat content in the body [4].Many research have reported that overweight and obese people have a low level of antioxidants in their blood compared with the general population, and there is an inverse relation between antioxidant concentration and body mass index (BMI) [5][6][7].The ingestion of high fruits and vegetables is linked with a lower prevalence of obesity and related symptoms and co-morbidities such as diabetes [8].Many studies suggest that obese people may have to take a large number of antioxidants to accomplish the lipids in the plasma as general-weight people [9].
Obesity and diabetes are becoming the twin epidemic crises globally.Several epidemiological studies reveal that parallel escalation of both metabolic disorders.Recent years have seen an increasing body of work on the following metabolic defects by these disorders that link the impaired tissue perfusion, sleep disturbance, altered vitamin D and micronutrients, and gastrointestinal (GI) tract issues [10].Diabetic neuropathy also affects the enteric nervous system (ENS) which promotes severe changes in digestive functionality such as motor, secretory/absorptive, and vascular changes [11].Particularly, the ENS is a part of the autonomic nervous system that comprises a neuronal network distributed across the GI tract all together with enteric glial cells (EGCs) [12,13].The EGCs are the non-neuronal cells that constitute the major part of ENS and are involved in physiological activities and homeostatic maintenance of the GI tract [13].
Enteric glia plays an important role as neuroprotective in ENS by secreting neuroprotective compounds such as antioxidant-reduced GSH.The GSH synthesis enzymes in the myenteric plexus with Lbuthionine sulfoximine inhibitor impact neuronal survival and inflammation.Both neurons and enteric glia possess the cellular machinery necessary for GSH synthesis [14].
As discussed EGCs provide metabolic support to the ENS neurons, and during gut motility protect their axons.It also noticed that in certain pathophysiological conditions, the EGCs might transdifferentiate into ENS neurons.Recent research revealed that EGCs possess immunological aspects and help patients with several immunological diseases of the gut [15].Though EGCs are non-immune cells and are capable of producing a variety of immunological responses such as cytokines and chemokines in the response to pathological stimuli, such as EGCs express Toll-like receptors (TLRs) including TLR2, TLR3, and TLR4 [16,17].EGC secretes interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, and C-C motif ligand 2 (CCL2) activated by microbial products such as lipopolysaccharides.EGCs generally respond to pro-inflammatory cytokines derived from macrophages and CD 4 + T cells.For example, IL-1β triggers the regulation of IL-6 and CCL2 in EGCs.Likewise, IFN-γ and lipopolysaccharides (LPS) co-stimulation of EGCs releases the IL-1β and IL-18 [18].Excess OS causes neurodegeneration and gut motility and how antioxidants supplementation mitigate these effects have been illustrated in Figure 1.
The GSH has complex metabolic and biochemical fates and is a cofactor for the many enzymes that function in modifying the obesity and diabetes responses.The GSH depletion may cause to increase the energy metabolism and reduce adipose accretion, while the elevated GSH peroxidase activity induces insulin resistance [19,20].
As per the World Health Organization (WHO), obesity is a state of agglomeration of ample fat in adipose tissues so that normal functioning of health can be deprived [21].Medically, obesity may explain the adult having a BMI greater than 30, but "the definition is not sufficient because it does not fully explain the regional dispensation of fat within the body such as abdominal/visceral vs. subcutaneous.Individuals who have similar total body fat and BMI do not mean they have similar abdominal fat.Abdominal fat agglomeration linked with increased risk of non-communicable diseases".
Abdominal obesity (AO) is linked with an increased inunction of free fatty acids (FFAs) from the visceral fat depot and metabolic overactivity (such as insulin resistance) [22].The overflow of FFAs to various organs may be caused by hyperlipolysis of hypertrophied intra-abdominal adipocytes.These conditions may lead to impairing liver function that may cause overproduction of liver glucose and insulin resistance.The liver insulin resistance may reduce the degradation of apolipoprotein B and increase the production of lipoprotein rich in triglycerides (TG) [23].In obese patients, the intrusion of macrophages occurs in adipose tissues, which may result in inflammation.Other factors may include IL-6 and TNF-α which may increase the inflammation markers of C-reactive protein in plasma [23].
The heavy fat mass may bring many difficulties such as slow locomotion and tiredness in a small distance walking, as back, hip, knee, ankle, and foot pain.On the knee joint, the tendons, and cartilage fascia all are affected because of increased body weight, which may result in osteoarthritis.An abnormal increase in body weight may also invite not only insulin resistance but also metabolic syndrome which are the major factors for cardiovascular diseases (CVDs) [24].
The recent finding suggests that increased body fat may increase the OS that can be assessed by urinary F-2 isoprostanes [25]; hence, the formed free radicals are the important etiology and carry forward the obesity-related comorbidities [26], and many studies show that antioxidant may have safeguarded effect on such conditions [27].
The past few decades and recent studies indicate an increase in obesity and diabetes which represent a major medical problem worldwide.As per the data available from the WHO, 422 million people anguished from diabetes.In 2019, 1.5 million death were directly reported from diabetes [28], 1.9 billion were overweight and more than 650 million adults were suffering from obesity [21].Several reports present both insulin resistance and impaired insulin release as the main factors for the onset of diabetes [type 2 diabetes mellitus (T2DM)].In obesity, insulin resistance occurs due to the permanent increase of plasma-FFAs and primary utilization of these lipids by the muscle that induces attenuation of glucose uptake.The increased blood glucose level is compensated by a rise in insulin secretion by the pancreas, and the dropdown in insulin secretion takes place as a late phenomenon [29].
In diabetes, it has been implicated that there is an imbalance between antioxidant scavenging activity and the formation of ROS.ROS are the end product produced during protein glycation and as a result of advanced glycation end-product receptor binding, which impairs the insulin signaling pathway and produces cytotoxicity in islets of Langerhans (especially in β-cells).However, these effects can be minimized by the increased intake of antioxidants.Many findings indicate that the intake of increased antioxidants is effective in minimizing the adverse effect of the disease [30].The association between unhealthy diets and OS and the interaction of antioxidants and immunity has been described in Figure 2. Taking into consideration the adverse impacts of diabetes and obesity and being overweight on human health, this study intends on groups of overweight/obese and diabetes subjects to find out the impact of serum/plasma antioxidant concentration and to determine further the influences of antioxidant intervention on demographic characteristics of these subjects.Therefore, we involved observational studies and randomized controlled trials (RCTs), primarily focusing on entities such as weight change, BMI change, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), fasting blood glucose level, glycated haemoglobin (HbA1c), and other parameters related to diabetes and obesity.The main objective of this systematic review is to find out the relationship between antioxidants in obesity and diabetes.And also, to find the association of antioxidants in neuro-gliopathies.

Materials and methods
The systematic review was carried out and summarized as per the recommendations governed by the preferred reporting items for systematic reviews and meta-analysis-PRISMA [31].The systematic literature review phase wise study has been described in Figure 3.

Data sources and search strategy
A broad search strategy was evolved to systematically recognize the studies on the action of antioxidants in diabetes and obesity or mitigate their effect using keywords and controlled vocabulary.
A literature search was done digitally on 8 June 2022 in the databases Google Scholar, and PubMed, reviewing all the articles published in English.There were no limitations to the study (such as study design, region, or any time frame).

Inclusion and exclusion criteria
The study included if they reach the mentioned criteria: Inclusion/exclusion criteria were based on screening of the titles, keywords, and abstracts of the primary search. ( We included all types of studies reporting the role of antioxidants, minerals, and vitamins having an antioxidant effect on patients suffering from obesity and diabetes. (2) The impact of the gut microbiome on antioxidant production and ENS protection.(3) Only included human studies.(4) Studies written in English were eligible to be included.Only full-text articles are included.(5) There is no limitation in the type of study.(6) The studies were excluded if they encountered the mentioned criteria: Studies written in languages other than English. (1) The studies on an experimental model like rats/mice.(2) We have excluded the data that represents or talks about lifestyle factors, antioxidants' effect on other diseases rather than diabetes and obesity, the plant extract effects, and those that do not meet our requirement of title. (3)

Results
The beginning database search picked out an aggregate of 2,428 articles, 1,310 in PubMed, 876 in Google Scholar, and 242 records from other sources.A total of 2,040 (total duplicates 388) was found after removing the duplicated articles, and after reading the title and abstracts were further decreased to 139 full-text articles.These 139 studies went for full-text analysis, which resulted in the exclusion of 123 studies and generated a final 16 articles included for systemic analysis, as depicted in the flowchart presented in Figure 4 and the bar graph in Figure 5.

Quality assessment
An overview of the 16 articles, that encounter the general inclusion criteria, and the detail of the studies such as author(s) & publication year, the aim of the study, country, study design/analysis, descriptions, outcomes, and findings that explicitly deal with the role of an antioxidant in diabetes and obesity is provided in Table 1.
There are three studies from Florida [32], two studies from Australia [33,36], UK [34], two studies from Mexico [35,42], Iran [37], Bangladesh [38], Denmark [39], two studies from New Zealand [40,47], Spain [41], Sweden [43], mixed studies from California, Colorado and Texas [44], Japan [45] and Turkey [46] are included in this paper.The bar diagram is illustrated in Figure 7.The articles published year-wise have been illustrated in the bar diagram Figure 8.Studies interlink the antioxidants and neuro-gliopathies in the gut and brain in diabesity has been described elaborately in Table 2, and the antioxidant supplements suppresses the OS and neuro-gliopathies has been elaborated in the Table 3.

Discussion
The GI manifestation of diabetes is very common and a source of discomfort and motility and almost every part of GI tract from the esophagus to the rectum causes a variety of symptoms such as heartburn, nausea, vomiting, diarrhea, abdominal pain, and constipation.So it is important to understand the underlying mechanism of diabetic gastroenteropathy [68].Over recent years, the data regarding diabetic gastroenteropathy has expanding and the role of ENS and autonomic neuropathy causing GI disturbance caused by the intestinal cells of Cajal and neurotransmission in diabetics [68].The enteric neurons are located at the different regions of the intestine and display the different susceptibilities to diabetic damage and insulin treatment, which highlight the neuronal microenvironment in the pathogenesis of diabetic neuropathy.Shift in the balancing of free radicals leads to OS in the gut which in turn leads to enteric neuropathy in diabetes [69].
The human gut consists of over 100 trillion microorganisms including 1,000 different species of bacteria, that play a crucial role pathophysiologically as well as physiologically in the host.An imbalance of GI ecosystem leads to contribute the development of several diseases such as Alzheimer's disease, depression, and diabetes [70].A study shows the connection between early disruption of the microbiome leads the GI distract function and increases the susceptibility of autism [71].An altered microbiome leads to immune system dysregulation, inflammation, OS, metabolic and methylation abnormalities as well as GI distress [71].In contrast to glial cells the central nervous system from the oxidative damage by synthesizing oxidants [72].The OS and associated brain diseases, the antioxidants rescue the neuronal cells from OS by neutralizing the ROS [73].

Association between carotenoid intake and obesity and diabetes
Seven studies (4 cross-sectional studies and 3 randomized control trials) examined the connection between dietary or plasma carotenoids and diabetes and obesity.Serum carotenoid such as β-carotenoid are known as indicators of fruit and vegetable ingestion and many results show that a higher intake of these products is effective against obesity [8] and its correlated problems such as diabetes and CVDs.Both the studies observational and randomized control trial studies followed the design either measurement of dietary consumption and serum concentration were evaluated and associated with BMI, WC, WHtR, or other measures were associated between serum carotenoid concentration and measures of adiposity.Canas et al. [32] investigated that increased concentration of β-carotene reflects a reduction in BMI z-score, WHtR, and visceral and subcutaneous adipose tissue.The MCS (contains 2,000 IU β-carotene and 500 µg of α-carotene, 10 mg of lutein, 2 mg zeaxanthin, and 10 mg of γ-tocopherol).The MCS brought about -0.19 ± 0.13 changes in BMI z-score with a P value of 0.024, 3% ± 2% deviation in WC, and 0.03 ± 0.03 reduction in the WHtR with P value of 0.039 at six months.β-Carotene was found in inverse relation with BMI z-score, WHtR, visceral, and subcutaneous adipose tissue at baseline with P values 0.003, 0.017, 0.023, and 0.045 [32].
Coyne et al. [33] summarized that the low level of serum carotene (such as α and β), and the sum of these carotenoids (such as α-carotene, lycopene, β-cryptoxanthin, zeaxanthin, and β-carotene) was linked with metabolic ailments.The person with metabolic syndrome has found significantly lower (P < 0.05) serum concentrations of α (with P = 0.25), and β-carotene (with P = 0.15) along with the sum of five carotenoids (P = 0.41).In current smokers, there was found no remarkable variation in carotenoid concentration and metabolic ailments, but in former and who did not smoke the α and β-carotene were found significantly lower with metabolic syndrome [33].
Another study reported by Daniels et al. [34] that excess ingestion of coloring fruits and green vegetables is linked with carotenoid concentration and also influences the enzyme-linked antioxidant properties of HDL.The group having ≥ 6 portions of colored fruits and green vegetables every day was found increased serum carotenoid, HDL2, and HDL3 (α-carotene, β-cryptoxanthin, lycopene, and lutein having P values 0.008, 0.042, 0.016, 0.042 and 0.012) the activities of LCAT and PON-1 in HDL3 (with P value 0.044 and 0.006).The study furnished mechanistic support for increased consumption of coloring fruits and green vegetables is effective in reducing the prevalences of diabetes and its associated CVD [34].
Similarly, Harari et al. [36] reported that there was a favorable relation between adipose tissues, metabolic health, and serum carotenoids level.Carotenoids found an inverse association with TG (r value was -0.22, and P = 0.051), and TG and serum retinol tended positively linked (r value was 0.22, and P = 0.051).ζ-Carotene in adipose tissue was found negatively associated with TG and phytofluene, and total carotenoid was found inverse association with serum TG.A total carotenoid found an inverse association with the HOMA-estimated insulin resistance (IR, HOMA-IR) and fasting insulin.ζ-Carotene shows an inverse relation with HbA1c (r value was -0.23, and P = 0.069) [36].
Another study reported by Östh et al. [43] that β-carotene concentration was lowered in the obese subject, and its lower concentration indicates adipocytes from T2DM subjects cause obesity.The β-carotene concentration was found 50 percent lower in adipocytes from the obese and diabetes group than in the other groups.Triacylglycerol was found in 92% ± 1% of adipocytes in the lean group whereas 99% ± 2% in the diabetic obese group (P < 0.05) [43].
One more randomized clinical trial study reported by Takagi et al. [45] concluded that dietary intake of carotenoid-rich vegetables helps in the reduction of intra-abdominal visceral fat.The result shows that the daily beverage intake raises the carotenoids in plasma level and reduces the visceral fat in all groups significantly.The WC was significantly lowered in the group that had high lycopene with low lutein, whereas the CoQ10 oxidation rate was significantly reduced in overall groups.Only in low lycopene with low lutein group had to differ in their gene expression profile that indicates the effect of carotenoids on genetic profile [45].
The most common carotenoids such as β-carotene, lutein, crocin, lycopene, zeaxanthin, and curcumin have antioxidants and anti-inflammatory properties in the management of neurodegenerative disorders [74,75].
People with diabetes may face enteric neuropathy caused by a decrease in the number of neurons in the ENS.A treatment strategy that can be used is antioxidants.Antioxidants help to promote redox balancing and decrease enteric neuron death.So, quercetin-loaded microcapsules (QLMs) are antioxidants with meticulous release in the gut.These QLMs promote controlled release and higher bioavailability of quercetin a good antioxidant with neuroprotective.A study was conducted on the effect of QLMs on enteric innervation and the oxidative status of the ileum of diabetic rats.The study showed a reduction in the carbonyl content and increased molecular weight of antioxidants (DQ 10 : diabetic groups treated with QLM at a dose of 10 mg/kg; and DQ 100 : diabetic groups treated with QLM at a dose of 100 mg/kg).The group treated with QLMs at the dose of 10 mg/kg had a significant result on the nitrergic neurons that reduce oxidative damage in diabetes [76].

Association between ascorbic acid intake and obesity and diabetes
Three cross-sectional studies and one prospective cohort study reported the connection between ascorbic acid and obesity and diabetes.Many studies revealed that a low content of ascorbic acid might be a risk factor for several disease mortality.One prospective cohort study by Larsen et al. [39] reported that there was no relation between ascorbic acid and body weight or WC, but ascorbic acid-rich diet may be weakly correlated with higher WC gain to the people genetically sensible to an increased WHtR.The result indicates no remarkable relation between dietary ascorbic acid and deviation in body weight or WC.An allele of the 14 waists to hip ratio associated SNPs was associated with an annual change in WC of 0.039 cm annually (P = 0.02, 95% confidence interval: 0.005 to 0.073) per 100 mg per day higher ascorbic acid consumption.However, the annual change in WC only remained borderline significant after adaptation for the annual change in body weight [39].
One more cross-sectional study by Wilson et al. [47] found out that the ascorbic acid requirement was greater in adults/patients with a history of prediabetes, type-II diabetes, obesity, and smokers.The results showed that the plasma ascorbic acid concentration was significantly less in T2DM (41.2 µmol/L) compared with NGT (57.4 µmol/L).In the prediabetes and T2DM groups, it was noticed that there was a high amount of vitamin C (< 11.0 µmol/L) was noted.The BMI, fasting glucose, dietary ascorbic acid intake, and smoking history (having P values of 0.001, 0.001, 0.032, and 0.003) were independent predictor of ascorbic acid serum concentration [47].García et al. [35] and Sanchez-Lugo et al. [44] reported the combined effect of ascorbic acid along with retinol, tocopherol, and zinc that will be described in the below section.
Neuropathic pain is the more common painful condition that happens after a lesion or an insult to the somatosensory nerve system.Recent studies showed that treatment with vitamin C showed a positive effect [1].One study showed, that in diabetic peripheral neuropathy, the mean visual analog score was significant in the treatment group (5.54 ± 0.81 vs. 6.72 ± 0.90; P < 0.0001) at 12 weeks [1].

Association between vitamin E intake and obesity and diabetes
One randomized clinical trial, two case-control, and one cross-sectional study reported the connection between tocopherol and obesity and diabetes.Tocopherol is a natural antioxidant and plays a beneficial role against ROS in the body's defense system.The low level of vitamin E is directly associated with increased central adiposity and related health problems such as diabetes CVD and many more.One randomized clinical trial by Manning et al. [40] reported that tocopherol enhances OS, insulin resistance, and hepatic cellular function in an overweight subject.The supplementation of 800 IU/day of tocopherol and placebo for three months, and after that further 1,200 IU/day of tocopherol dose was increased for three months.The result shows that plasma peroxidation decreased by 27% in the first three months and by 29% at 6 months.At three months it was noticed that the fasting glucose level and insulin concentration were significantly reduced but these things were not happening with six months of supplementation.Throughout the study, the alanine transaminase concentration was declining.The vitamin E supplementation was not significant in the subjects receiving the doses and their WC (P = 0.82) and BMI (P = 0.87), but the insulin concentrations and fasting plasma glucose were significantly reduced (r = 0.235, P = 0.04) [40].
Another case-control trial by Mansego et al. [41] reported that WC is linked with dietary tocopherol intake in the obese subject.In the AO group, it was found that 8-oxo-2'-deoxyguanosine was at higher levels, and were taking lower retinol and tocopherol compared to the non-AO group.Logistic regression analysis indicates that TXN and COMT were linked with WC and AO.Moreover, these polymorphisms were more firmly linked with changes in WC in subjects having a lower intake of tocopherol.WC is linked both with dietary tocopherol ingestion and genetic variants of COMT and TXN proposing the presence of a complex nutrigenetic pathway that regulates AO [41].Hekmat et al. [37] and Sanchez-Lugo et al. [44] reported the combined effect of tocopherol along with retinol, and ascorbic acid that will be described in the below section.
A study was conducted on the ileum of diabetic rats to investigate the effect of vitamin E (1 g/kg body weight) supplementation on myosin-V and neuronal nitric oxide synthase immunoreactive myenteric neurons.The diabetic group treated with vitamin E showed increased size of nitrergic neurons, and the neuronal density was found higher by 27% in a nor-glycemic treated vitamin-E group than the norglycemic group (P < 0.05).The result showed that vitamin E elicited a neuroprotective and neurotrophic effect on the natural aging process [77].
A peripheral nerve injury is a very common complication during trauma that requires a functional recovery and regeneration.So, it is necessary to find a suitable material that would promote peripheral nerve regeneration due to the shortage of capacity for peripheral nerve regeneration.So, that's why magnesium attracted with good biocompatibility and appropriate degradability to increase attention during the past years [78].

Association between a combination of vitamin A, tocopherol, ascorbic acid, and zinc intake and obesity and diabetes
A cross-sectional study by García et al. [35] investigated that a combination of zinc, retinol, and ascorbic acid were linked with adiposity, obesity, and leptin concentration in women.The prevalences of overweight and obesity were found at 36% and 44% (with BMI > 25 kg/m 2 and BMI > 30 kg/m 2 ), whereas the prevalences of zinc, ascorbic acid, and tocopherol were similar in these patients but no vitamin A deficiency was found in them.It was noticed that ascorbic acid was inversely linked with BMI, WHtR, and leptin (P < 0.05), whereas retinol was directly linked with leptin (P < 0.05).The leptin concentration was linked with lower zinc and ascorbic acid concentration in obese women (P < 0.05) and vitamin A concentration was higher in non-obese women (P < 0.01).Whereas tocopherol was not associated with any obesity markers [35].Sanchez-Lugo et al. [44] concluded that there was no significant relation between improved IS and intake of tocopherol and ascorbic acid.The Pearson correlation coefficient for vitamin C and E about IS was r value of 0.07 (P = 0.02) and an r value of 0.07 (P = 0.01) respectively [44].
Hirschsprung disease is a severe disease of ENS development caused by the nonfunctioning of ENS precursor migration into distal bowel aganglionosis (DBA).Depletion of vitamin A causes DBA in serum retinol-binding-protein-deficient (Rbp4 -/-) mice.RA decreases the phosphatase and tensin homolog (Pten) accumulation in migrating cells.This Pten overexpression decreases the ENS precursor migration.So, the study showed the deficiency of vitamin A deficiency is a no-genetic risk factor that causes the Hirschsprung disease's penetrance and expressivity [79].
One more case-control study by Hekmat et al. [37] investigated that retinol was remarkably lower in diabetic pregnant women in comparison with the control group, and this is due to lowered antioxidant concentration in GDM women.
Zinc is another essential micronutrient that has a beneficial role in various physiological processes such as tissue repair, cellular immunity, and cell development [35].And, few studies reported that zinc is linked with the degree of obesity [80].A low plasma zinc level is linked with excess fat deposition and reduces lean mass accrual [81].Islam et al. [38] reported that low serum zinc highlighted the increase in insulin resistance with increasing BMI.Serum zinc concentration was less in prediabetic to normal (65 ppb/L) compared with diabetic (33 ppb/L).Multiple linear regression shows lower zinc levels in prediabetes than in those with normal blood glucose levels.Linear regression for HOMA parameters did not show any statistical connection between zinc level, insulin resistance (P = 0.08), and β-cell function (P = 0.07) [38].The copper and vitamin B 12 deficiency associated with myeloneuropathy mimicking subacute without cognitive dysfunction [82].
A study was conducted on myenteric in the jejunum of diabetic rats to evaluate the synergetic effect of the association of vitamin C and tocopherol.The rats from the normoglycemic treated with ascorbic acid and α-tocopherol and the diabetic treated with ascorbic acid and α-tocopherol group were supplemented with 1 g ascorbic acid/L in water and 1% α-tocopherol in chow.The supplementation of these helps to prevent the cell loss of myenteric neurons expressing HuC/D and TrkA equally.They observed a reduction of calcitonin gene related peptide (CGRP) nerve fiber varicosities and prevention of increased cell body size of vasoactive intestinal polypeptide (VIP) neurons (P < 0.05) [83].
In conclusion, this literature search of present studies shows the interconnection between antioxidant intake among obese and diabetes.The enteric glia and neurons both express the cellular mechanism for GSH synthesis and glial GSH synthesis is necessary for neuronal survival in isolated ENS.The GSH has complex metabolic and biochemical fates and is a cofactor for the many enzymes that function in modifying the obesity and diabetes responses.The GSH depletion may cause to increase the energy metabolism and reduce adipose accretion, while the elevated GSH peroxidase activity induces insulin resistance.Over recent years, the data regarding diabetic gastroenteropathy is expanding, and the role of ENS and autonomic neuropathy causing GI disturbance caused by the intestinal cells of Cajal and neurotransmission in diabetics.The enteric neurons are located at the different regions of the intestine and display the different susceptibilities to diabetic damage and insulin treatment, that highlight the neuronal microenvironment in the pathogenesis of diabetic neuropathy.Shift in the balancing of free radicals leads OS in the gut which in turn leads to enteric neuropathy in diabetes.Emerging studies reports indicate that natural antioxidants can modulate OS and improve immune function in obesity and diabetes.The findings indicate both obese and diabetic patients have a minimum content of antioxidants, especially carotenoids, retinol, ascorbic acid, tocopherol, magnesium, and zinc.While few research illustrated that ingestion of the abovementioned antioxidants was lowered among diabetes and obese subjects in contrast with their normal-weight population, this was not endorsed by every study.However, most of the studies including observational and randomized control trials reported the positive effect of antioxidant intake and its management on obesity and diabetes subjects as immunity boosters.

Figure 1 .
Figure 1.Excess OS causes neurodegeneration and gut motility.TNF-α: tumor necrosis factor-α; ROS: reactive oxygen species.The image was created with the help of Biorender.com

Figure 2 .
Figure 2. Unhealthy diets and OS and the interaction of antioxidants and immunity.LDL: low-density lipoprotein.The image was created with the help of Biorender.com

Figure 3 .
Figure 3. Systematic literature review phase wise study

Figure 4 .
Figure 4. PRISMA flow chart outlines the funnelling and identification of relevant studies

Figure 5 .
Figure 5.The bar diagram of the systematic review, inclusion, and exclusion studies in the review

Figure 6 .
Figure 6.Indicating the types of studies included in this systematic review

Figure 7 .Figure 8 .
Figure 7.Primary location of the studies included in this review

Table 1 .
Study characteristics for selected studies (continued)

Table 1 .
Study characteristics for selected studies (continued)

Table 1 .
Study characteristics for selected studies (continued)

Table 1 .
Study characteristics for selected studies (continued)

Table 1 .
Study characteristics for selected studies (continued)

Table 2 .
Studies interlink the antioxidants and neuro-gliopathies in the gut and brain in diabesity

Table 3 .
Antioxidants in suppressing the OS and neuro-gliopathies