Comparing the renoprotective effects of the antioxidants melatonin, vitamin D and vitamin E in diabetic rats

Abdulmonim A Alqasim, Essam Eldin M Nour Eldin, Sami H Hammadi, Ghada E Esheba

J Taibah Univ Med Sci . 2020 Jul 17;15(5):351-357. doi: 10.1016/j.jtumed.2020.05.007. eCollection 2020 Oct.


Objectives: Diabetes mellitus is associated with oxidative stress that leads to inflammation and diabetic nephropathy. This study aimed to determine the possible renoprotective effects of the antioxidants melatonin, vitamin D and vitamin E in diabetic rats.

Methods: We divided 108 albino rats into 12 groups. G1 group was fed a normal diet and did not receive any medication. G2 to G4 consisted of non-diabetic rats that were treated as follows: G2 with melatonin; G3 with vitamin E; G4 with vitamin D. Groups G5 to G12 consisted of diabetic rats that were treated as follows: G5 received no medication; G6 treated with insulin; G7 treated with melatonin; G8 treated with melatonin and insulin; G9 treated with vitamin E; G10 treated with vitamin E and insulin; G11 treated with vitamin D and G12 treated with vitamin D and insulin. Two months after treatment commenced, histological and biochemical examinations of glucose profile, oxidative stress status, renal function, homocysteine and TNF-α were performed.

Results: Total antioxidant capacity (TAC) increased significantly in groups G2, 7, 8, 10 and 11. TNF-α significantly increased in G2, but decreased in all other groups. Creatinine increased significantly in groups G5, 6, 7, 8, 9, 11 and 12. In the kidneys of the diabetic rats, thickened capillary basement membrane, diffuse mesangial sclerosis and nodular glomerulosclerosis was observed. Rats treated with melatonin showed marked improvement in these symptoms. However, in those treated with vitamin D and E, thickened capillary basement membrane and mesangial sclerosis was still present.

Conclusions: Melatonin, administered either with or without insulin had a significant biochemical antioxidant effect and histological renoprotective effect. Conversely, vitamin D and E did not appear to have any effects on the parameters measured.

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Effect of Vitamin C and E on Oxidative Stress and Antioxidant System in the Salivary Glands of STZ-induced Diabetic Rats

Flavia Kazue Ibuki, Cassia T Bergamaschi, Marlus da Silva Pedrosa, Fernando Neves Nogueira

Arch Oral Biol . 2020 Aug;116:104765. doi: 10.1016/j.archoralbio.2020.104765. Epub 2020 May 16.


Objective: We examined the effects of vitamin C and E supplementation in the prevention of oxidative stress in the salivary glands of STZ-induced diabetic rats.

Design: Forty-eight male Wistar rats were divided into six groups (n = 8 in each): control (C), control supplemented with vitamin C (Cvc) and E (Cve), diabetic (D), and diabetic supplemented with vitamin C (Dvc) and E (Dve). Vitamin C (150 mg/kg) and E (300 mg/kg) were daily administered for 21 days. Serum ascorbic acid and α-tocopherol levels were quantified. Glandular levels of hydrogen peroxide (H2O2), superoxide anion (O2), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), malondialdehyde (MDA) and the total antioxidant status (TAS) were estimated.

Results: Vitamin C and E levels were reduced in D group. Vitamin C decreased the levels of O2 in the salivary gland of diabetic rats. Vitamin E increased the concentration of O2 in PA gland of diabetic animals. In the SM gland of the diabetic group, MDA, SOD, GPx and TAS increased. Dve presented reduced SOD activity and increased GR, GPx, and MDA. Dve increased GPx, Gr and TAS levels. In the PA gland, MDA, SOD, CAT, GPx, GR, and TAS were similar in C and D. TAS, SOD, CAT, GPx, and GR increased in Dvc. Vitamin E supplementation resulted in increased MDA and CAT levels and reduced SOD activity.

Conclusion: In the SM glands of the diabetic rats, vitamin C supplementation improved the antioxidant system, while vitamin E acted as pro-oxidant.

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Effect of Folic Acid and Vitamin E on Promoter DNA Methylation and Expression of TGF-β1, ESR-1 and CDH-1 in the Uterus of STZ-induced Diabetic Rats

Maryam Tabebordbar, Mostafa Moradi Sarabi, Sina Vakili, Razieh Zare, Fatemeh Zal

Arch Physiol Biochem . 2020 May 29;1-7. doi: 10.1080/13813455.2020.1770798.


The present study is the first attempt made to investigate the effects of diabetes on expression and promoter DNA methylation of TGF-β1, ESR-1, and CDH-1 genes and also the effects of folic acid (FA) and vitamin E (Vit E) supplementations on improving diabetes mellitus. STZ-induced diabetic rats were treated with Vit E (200 mg/kg/day) and FA (25 mg/kg/day) for 8 weeks and expression and DNA methylation of TGF-β1, ESR-1, and CDH-1 genes in uterus were analysed. Data indicated that diabetes increases the expression of TGFβ-1 and ESR-1 and decreases CDH-1 expression and TGFβ-1 promoter methylation in the uterus of rats. Vit E and FA improved the negative effects of diabetes by decreasing the expression of TGFβ-1 and ESR-1 and increasing that of CDH-1 in diabetic rats. In conclusion, these findings emphasise that Vit E and FA supplementations could improve negative effects caused by diabetes on uterus function and fertility in diabetic rats.

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The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetic Neuropathy: A Phase II Randomized Controlled Trial

Yeek Tat Ng, Sonia Chew Wen Phang, Gerald Chen Jie Tan, En Yng Ng, Nevein Philip Botross Henien, Uma Devi M Palanisamy, Badariah Ahmad, Khalid Abdul Kadir

Nutrients . 2020 May 23;12(5):1522. doi: 10.3390/nu12051522.


Chronic hyperglycemia increases oxidative stress, activates inflammatory pathways and reduces nerve growth factor (NGF) among diabetic patients, which contribute to development of diabetic peripheral neuropathy (DPN). Tocotrienol-Rich Vitamin E (Tocovid) possesses potent antioxidant and anti-inflammatory properties which are postulated to target these pathogeneses in order to ameliorate DPN. This study aims to evaluate the effects of Tocovid on nerve conduction parameters and serum biomarkers among diabetic patients. This multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial was conducted on 80 eligible participants. The intervention group (n = 39) was randomly allocated to receive 200 mg of Tocovid twice a day, and the control group (n = 41) received placebo twice a day. At the end of eight weeks, the nerve conduction parameters, as assessed by nerve conduction study, as well as serum biomarkers (NGF, malondialdehyde, vascular cell adhesion molecule 1, tumor necrosis factor receptor 1 and thromboxane B2) were compared between the two groups. Compared to placebo, Tocovid significantly improves the nerve conduction velocities of all nerves (+1.25 m/s, interquartile range [IQR] 3.35, p < 0.001, median nerve; +1.60 m/s, IQR 1.80, p < 0.001, sural nerve; +0.75 m/s, IQR 2.25, p < 0.001, tibial nerve). Meanwhile, the levels of serum NGF were significantly higher in the Tocovid group as compared to placebo at eight weeks post-intervention. Participants receiving Tocovid illustrated highly significant improvement in terms of nerve conduction velocities for all nerves tested after eight weeks of supplementation. In addition, Tocovid supplementation elevated the levels of serum NGF, in which its increase is postulated to reflect enhanced neuronal functions. This novel finding suggests that Tocovid could be a disease-modifying agent targeting serum NGF to improve nerve conduction velocities.

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Effect of High Fructose-Induced Metabolic Syndrome on Tissue Vitamin E and Lipid Peroxide Levels in Rats

Akira Kitagawa, Yoshiji Ohta, Koji Ohashi, Koji Yashiro, Kenji Fukuzawa

J Nutr Sci Vitaminol (Tokyo) . 2020;66(2):200-206. doi: 10.3177/jnsv.66.200.


In the present study, we examined the effect of high fructose-induced metabolic syndrome (MetS) on tissue vitamin E and lipid peroxide (LPO) levels in rats. Feeding of a diet containing 60% fructose (HFD) to Wistar rats for 2, 4, and 6 wk caused week-dependent increases in HOMA-IR score and serum insulin, triglyceride, total cholesterol, and free fatty acid concentrations. Each week HFD feeding increased serum vitamin E concentration. Six-week HFD feeding reduced vitamin E status (the serum ratio of vitamin E/triglyceride+total cholesterol). Four- and 6-wk HFD feeding increased serum LPO concentration. Two-week HFD feeding increased liver, heart, kidney, and skeletal muscle (SM) vitamin E contents and decreased white adipose tissue (WAT) vitamin E content. Four- and 6-wk HFD feeding further reduced WAT vitamin E content without affecting the increased kidney and SM vitamin E contents. Six-week HFD feeding reduced the increased liver and heart vitamin E contents below the level of non-HFD feeding. Four-week HFD feeding increased heart and WAT LPO contents. Six-week HFD feeding increased liver LPO content and further increased heart and WAT LPO contents. Kidney and SM LPO contents remained unchanged. These results indicate that HFD-rats with early MetS have increased liver, kidney, heart, and SM vitamin E contents and decreased WAT vitamin E content under unchanged tissue LPO content and vitamin E status, while HFD-fed rats with progressed MetS have both decreased liver, heart, and WAT vitamin E contents under increased tissue LPO content and disrupted vitamin E status.

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Non-alcoholic Fatty Liver Disease and Diabetes Mellitus

Gebran Khneizer, Syed Rizvi, Samer Gawrieh

Adv Exp Med Biol . 2020 May 19. doi: 10.1007/5584_2020_532.


Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading liver disease globally. NAFLD patients can have a progressive phenotype, non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis, liver failure and cancer. There is a close bi-directional relationship between NAFLD and type 2 diabetes mellitus (T2DM); NAFLD increases the risk for T2DM and its complications whereas T2DM increases the severity of NAFLD and its complications. The large global impact of NAFLD and T2DM on healthcare systems requires a paradigm shift from specialty care to early identification and risk stratification of NAFLD in primary care and diabetes clinics. Approach to diagnosis, risk stratification and management of NAFLD is discussed. In addition to optimizing the control of coexisting cardiometabolic comorbidities, early referral of NAFLD patients at high risk of having NASH or significant fibrosis to hepatology specialist care may improve management and allow access for clinical trials. Lifestyle modifications, vitamin E, pioglitazone and metformin are currently available options that may benefit patients with T2DM and NAFLD. The burst of clinical trials investigating newer therapeutic agents for NAFLD and NASH offer hope for new, effective and safe therapies in the near future.

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Impact of Vitamin E Supplementation on Vascular Function in Haptoglobin Genotype Stratified Diabetes Patients (EVAS Trial): A Randomised Controlled Trial

Rinkoo Dalan, Liuh Ling Goh, Chien Joo Lim, Aruni Seneviratna, Huiling Liew, Cherng Jye Seow, Lian Xia, Daniel E K Chew, Melvin K S Leow, Bernhard O Boehm

Nutr Diabetes . 2020 Apr 27;10(1):13. doi: 10.1038/s41387-020-0116-7.


Aims: Vitamin E (Vit-E) may preferentially improve cardiovascular risk in haptoglobin 2-2 (Hp2-2) genotype diabetes individuals. We studied the impact of Vit-E supplementation on vascular function in diabetes individuals stratified by haptoglobin genotype in Singapore.

Methods: In this 24-week, double blind, placebo-controlled RCT, we recruited 187 subjects (101 Hp2-2, 86 non-Hp2-2).

Intervention: alpha-tocopherol-400 IU.

Primary outcome: Change in EndoPAT-derived reactive-hyperaemia index (RHI) and augmentation index (AIx); Secondary Outcomes: Pulse-Wave velocity (Sphygmocor-PWV), carotid intima media thickness (CIMT), inflammation (hsCRP), derivatives of reactive-oxygen metabolites (dROMs), biological antioxidant-potential (BAPs), HbA1c, LDL-C, HDL-C and oxidised LDL-C (ox-LDL).

Results: Overall, with Vit-E supplementation no significant change in RHI, PWV, CIMT, hsCRP, dROMS, BAPs, HDL-C and HbA1c was observed (p > 0.05); an increase in LDL-C with concomitant decrease in ox-LDL, and incidentally increase in eGFR was observed (p < 0.05). No interaction effect with haptoglobin genotype was seen for all outcomes (p > 0.05). Subgroup analysis: In the non-Hp-2-2 group, Vit-E supplementation led to a higher EndoPAT-derived AIx, accompanied by higher LDL and ox-LDL concentrations (p < 0.05); Hp2-2 group: Vit-E supplementation led to higher eGFR when compared to the non-Hp2-2 group (exploratory) (p < 0.05). We observed an interaction effect for baseline haptoglobin concentration (threshold > 119 mg/dl) with intervention in terms of increased EndoPAT-derived AIx in the Hp > 119 mg/dl group whereas no change in the group with Hp ≤ 119 mg/dl.

Conclusion: Vit-E supplementation did not show any preferential benefit or deleterious effect on vascular function in Hp2-2 diabetes subjects in Singapore. A possible deleterious effect of an increase in arterial stiffness in individuals with Hp > 119 mg/dl was observed. Future studies should consider personalisation based on baseline Hp concentrations in patients with T2DM rather than just Hp2-2 genotype to evaluate impact on the detailed lipid pathways, cardiac and renal physiology. The impact of ethnic differences needs to be explored in greater details.

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Influence of omega-3 fatty acid and vitamin co-supplementation on metabolic status in gestational diabetes: A meta-analysis of randomized controlled studies

Li F, Pei L, Huang G, Ye H

Eur J Obstet Gynecol Reprod Biol. 2020 Apr;247:191-197. doi: 10.1016/j.ejogrb.2020.02.024. Epub 2020 Feb 26.



Omega-3 fatty acid and vitamin E or D co-supplementation may be an important approach to improve metabolic status in gestational diabetes, but the results are conflicting. This systematic review and meta-analysis was conducted to evaluate the effect of omega-3 fatty acid and vitamin co-supplementation on metabolic status in gestational diabetes.


PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials (RCTs) assessing the influence of omega-3 fatty acid and vitamin co-supplementation compared with placebo on metabolic status in gestational diabetes were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies.


Four RCTs were included in the meta-analysis. Compared with control interventions for gestational diabetes, omega-3 fatty acid and vitamin E or D co-supplementation was associated with significantly reduced fasting plasma glucose [mean difference (MD) -10.47, 95 % confidence interval (CI) -15.33 to -5.61, p < 0.0001], homeostasis model of assessment-insulin resistance (MD -1.6, 95 % CI=-2.44 to -0.77, p = 0.0002), malondialdehyde (MD -1.00, 95 % CI -1.05 to -0.95, p < 0.00001) and triglycerides (MD 26.22, 95 % CI -38.94 to -13.51, p < 0.0001), as well as increased antioxidant capacity (MD 173.51, 95 % CI 164.72-182.30, p < 0.00001), but showed no obvious effect on nitric oxide (MD 5.95, 95 % CI -7.48 to 19.37, p = 0.39) or total cholesterol (MD 1.63, 95 % CI -13.46 to 16.72, p = 0.83).


Omega-3 fatty acid and vitamin co-supplementation may have a favourable effect on metabolic status in gestational diabetes.

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Protective Effect of Palm Oil-Derived Tocotrienol-Rich Fraction Against Retinal Neurodegenerative Changes in Rats with Streptozotocin-Induced Diabetic Retinopathy

Sadikan MZ, Nasir NAA, Agarwal R, Ismail NM

Biomolecules. 2020 Apr 5;10(4). pii: E556. doi: 10.3390/biom10040556.


: Oxidative stress plays an important role in retinal neurodegeneration and angiogenesis associated with diabetes. In this study, we investigated the effect of the tocotrienol-rich fraction (TRF), a potent antioxidant, against diabetes-induced changes in retinal layer thickness (RLT), retinal cell count (RCC), retinal cell apoptosis, and retinal expression of vascular endothelial growth factor (VEGF) in rats. Additionally, the efficacy of TRF after administration by two different routes was compared. The diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin. Subsequently, diabetic rats received either oral or topical treatment with vehicle or TRF. Additionally, a group of non-diabetic rats was included with either oral or topical treatment with a vehicle. After 12 weeks of the treatment period, rats were euthanized, and retinas were collected for measurement of RLT, RCC, retinal cell apoptosis, and VEGF expression. RLT and RCC in the ganglion cell layer were reduced in all diabetic groups compared to control groups (p < 0.01). However, at the end of the experimental period, oral TRF-treated rats showed a significantly greater RLT compared to topical TRF-treated rats. A similar observation was made for retinal cell apoptosis and VEGF expression. In conclusion, oral TRF supplementation protects against retinal degenerative changes and an increase in VEGF expression in rats with streptozotocin-induced diabetic retinopathy. Similar effects were not observed after topical administration of TRF.

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Association of Circulating Retinol and α-TOH Levels with Cognitive Function in Aging Subject with Type 2 Diabetes Mellitus

Huang X, Guo Y, Li P, Ma X, Dong S, Hu H, Li Y, Yuan L.

J Nutr Health Aging. 2020;24(3):290-299. doi: 10.1007/s12603-020-1328-1.



Malnutrition of vitamin A (retinol) and vitamin E (α-tocopherol, α-TOH) was observed in type 2 diabetes mellitus (T2DM) or dementia patients. However, how these vitamins affect cognitive function of subjects with T2DM was seldom reported. The objective of this study was to determine the association of circulating retinol and α-TOH with cognition in aging subjects with T2DM.


A total of 448 T2DM subjects and 448 age, gender and education matched control subjects (aged 55-75 years) were included in the study. Demographic characters of the participants were collected. Food frequency questionnaire (FFQ) method was used to collect dietary intake information. To assess the status of cognition, the MoCA test was used. Circulating retinol and α-TOH levels were compared between T2DM and non-T2DM subjects. Correlation of circulating retinol and α-TOH levels with cognitive function was analyzed in T2DM subjects. The effect of serum retinol and α-TOH levels on the risk of MCI in T2DM patients was explored.


We found that T2DM-MCI subjects demonstrate lower serum retinol level than T2DM-nonMCI subjects (P < 0.01). Serum retinol level was positively correlated to cognitive function in T2DM subject (P < 0.05). T2DM subjects with higher circulating retinol level demonstrate higher cognitive scores in visual and executive, attention, language, memory and delayed recall domains (P < 0.05).


Diminished circulating retinol predicts an increased risk of MCI in T2DM patients. Our findings provide suggestions that optimal retinol nutritional status might benefit cognition and decrease the risk of MCI in aging subjects with T2DM.

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