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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

INTRODUCTION:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

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.

Abstract

: 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.

Abstract

OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSION:

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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Vitamin E Intake Is Associated with Lower Brain Volume in Haptoglobin 1-1 Elderly with Type 2 Diabetes

Livny A, Schnaider Beeri M, Heymann A, Moshier E, Berman Y, Mamistalov M, Shahar DR, Tsarfaty G, Leroith D, Preiss R, Soleimani L, Silverman JM, Bendlin BB, Levy A, Ravona-Springer R

J Alzheimers Dis. 2020 Feb 12. doi: 10.3233/JAD-191294. [Epub ahead of print]

Abstract

BACKGROUNDS:

The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype.

OBJECTIVE:

To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes.

METHODS:

Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n = 24, Hp 2-1: n = 77, Hp 2-2: n = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype.

RESULTS:

Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus’ volume; p = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p = 0.0348), increased by 0.429% for Hp 2-1 (p = 0.0457), and by 0.077% for Hp 2-2 (p = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p = 0.6011) and superior (p = 0.2025) frontal gyri or for the middle temporal gyrus (p = 0.503).

CONCLUSIONS:

The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype.

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A light microscopic investigation of the renoprotective effects of α-lipoic acid and α-tocopherol in an experimental diabetic rat model

Kayhan Kuştepe E, Bahar L, Zayman E, Sucu N, Gül S, Gül M

Biotech Histochem. 2020 Feb 4:1-12. doi: 10.1080/10520295.2019.1695942. [Epub ahead of print]

Abstract

We investigated the effects of α-lipoic acid (AL) and α-tocopherol (AT) on renal histopathology in a streptozotocin (STZ) induced diabetic rat model. Adult male rats were divided into six groups: group 1, saline only; group 2, AL only; group 3, AT only; group 4, STZ only; group 5, STZ + AL; group 6 STZ + AT. Experimental diabetes was induced by STZ. AL and AT were administered for 15 days. Kidney sections were examined using a light microscope after hematoxylin and eosin (H & E), periodic acid-Schiff (PAS) and caspase-3 staining. Histological damage to glomeruli, tubule epithelial cells and basement membrane was observed in group 4. Administration of AT and AL reduced renal injury in the diabetic rats. Group 5 exhibited a greater curative effect on diabetic rats than group 6. AT and AL may be useful for preventing diabetic renal damage.

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