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).

The search term for Google Scholar are “antioxidants and obesity”, “vitamin C and obesity”, “vitamin E and obesity”, “tocopherol and obesity”, “carotenoids and obesity”, “ascorbic acid and obesity”, “mineral antioxidants and obesity”, “zinc and obesity”, “magnesium and obesity”, “selenium and obesity”, “antioxidants and diabetes”, “antioxidant and diabetes mellitus”, “antioxidant and blood glucose”, “antioxidant and type 2 diabetes”, “plant-based antioxidants” and “obesity and diabetes”.

The final search for PubMed was ((vitamin C) and (diabetes)) and (obesity), (antioxidant) and (“diabetes and obesity”), (vitamin E) and (diabetes and obesity), (carotenoid) and (diabetes and obesity), (mineral) and (“diabetes and obesity”), (zinc) and (“diabetes and obesity”), (magnesium) and (“diabetes and obesity”), (selenium) and (“diabetes and obesity”), (plant-based antioxidant) and (“diabetes and obesity”).

The study included if they reach the mentioned criteria:

(1)

Inclusion/exclusion criteria were based on screening of the titles, keywords, and abstracts of the primary search.

The studies were excluded if they encountered the mentioned criteria:

(1)

Studies written in languages other than English.

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.

Most of the studies found cross-sectional studies [33, 35, 38, 42–44, 47], randomized control trials [32, 34, 40, 45, 46], case control [37, 41], and cohort study [36, 39]. The bar diagram is illustrated in Figure 6.

Obesity and related complications [32, 35, 39, 41, 44], diabetes and related complications [34, 37, 38, 42, 44], and the studies included both diabetes and obesity and related complications [33, 36, 40, 43, 46, 47]. Most of the studies included antioxidants such as carotenoids [32–34, 36, 42, 43, 45], vitamin C [35, 39, 44, 47], vitamin E [37, 40, 41, 44], zinc [35, 38], vitamin A [35, 38] and one study on magnesium [46].

The study on outcome measures include BMI [32, 33, 35, 39, 40, 42–47], WHR/WC [32, 33, 35, 39, 41, 46, 47], abdominal fat/visceral fat [32, 36, 42, 47]. Lipid level including HDL, very LDL (VLDL) or LDL [33–35, 42, 43, 47], body composition was assessed by dual X-ray absorptiometry [36], blood glucose level [33–35, 37, 42], insulin resistance [32, 36, 40, 46], HbA1c [38, 46, 47], HOMA [38, 43] and IS by minimal model analysis [44].

The participants of the study were diverse. The study only included smokers [33], pregnant women [37], CVD [34], and CKD [46].

The share of women and men in the study also differed. Three studies included only women [35, 37, 43], two studies included only children [32, 42], and another one, only men [45]. In the remaining ten studies, representatives of both sexes were recruited [33, 34, 36, 38, 39, 40, 41, 44, 46, 47].

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.

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].

Similarly, one more study by Mummidi et al. [42] reported that the response surface methodology showed increased α and β-carotenoids had a maximum effect on IS index compared with β-cryptoxanthin or lycopene. The concentration of β-cryptoxanthin and lycopene were [h² = 0.58, P = 1 × 10^–7 and h² = 0.98, P = 7 × 10^–18]. The study found a negative phenotypic correlation (P ≤ 0.05) between β-cryptoxanthin and five cardiometabolic risk factors (such as BMI, WC, fat mass, fasting glucose of –0.22, –0.25, –0.18, –0.23, –0.09 and positive correlation with HDL (0.29), whereas the lycopene showed a positive association with HDL (0.18) and negative association with fasting blood glucose (–0.08) [42].

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 (DQ₁₀: diabetic groups treated with QLM at a dose of 10 mg/kg; and DQ₁₀₀: 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].

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].

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 nor-glycemic group (P < 0.05). The result showed that vitamin E elicited a neuroprotective and neurotrophic effect on the natural aging process [77].

One randomized control trial reported the association between magnesium and obesity and diabetes. Magnesium is an important trace element linked with cellular enzymatic activity, especially glycolysis, and stimulates adenosine triphosphatase. Toprak et al. [46] reported that magnesium supplementation in CKD (suffering from hypomagnesemia) patients with obesity and diabetes help to improve their metabolic status. The result shows that the group having magnesium compared with placebo had significantly decreased insulin resistance (–24.5 vs. –8.2 percent, P = 0.007), insulin (–29.6 vs. –2.66 percent, P < 0.001), HbA1c (–6.6 vs. –0.16 percent, P < 0.001), WC (–4.8 vs. 0.55 percent, P < 0.001), whereas magnesium (0.21 mg/dL ± 0.18 mg/dL vs. –0.04 mg/dL ± 0.05 mg/dL, P < 0.001) and albumin (0.91% vs. –2.91%, P = 0.007) were remarkably increased [46].

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].

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/m² and BMI > 30 kg/m²), 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 B₁₂ 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.