The effects of vitamin E on non-proliferative diabetic retinopathy in type 2 diabetes mellitus: Are they sustainable with 12 months of therapy

J-Ian Ho, En Yng Ng, Yilynn Chiew, Yan Yi Koay, Pei Fen Chuar, Sonia Chew Wen Phang, Badariah Ahmad, Khalid Abdul Kadir

SAGE Open Med . 2022 May 26;10:20503121221095324. doi: 10.1177/20503121221095324. eCollection 2022.

Abstract

Introduction: Prolonged uncontrolled hyperglycaemia has shown to cause oxidative stress, inflammation, thrombosis and upregulation of angiogenesis in diabetics, which all contributes to diabetic retinopathy development and progression. Vitamin E is found to have anti-inflammatory, anti-oxidative, anti-thrombogenic and anti-angiogenesis which could play an important role in early treatment of diabetic retinopathy. This study aims to investigate the effect of Tocotrienol-rich vitamin E (Tocovid) on the progression of retinal microhaemorrhages and diabetic macular oedema in patients with diabetic retinopathy.

Method: This is a multi-centred, randomized, double-blinded, placebo-controlled trial which involved 55 eligible participants. The participants in the treatment group (n = 22) received Tocovid 200 mg twice daily while those in the placebo group (n = 23) would receive placebo twice daily. Both groups will be on the treatment for a total duration of 12 months. Both retinal signs will be assessed at baseline, 2 months, 6 months and 12 months of treatment to determine the progression of diabetic retinopathy. Serum vascular endothelial growth factor which reflects on the angiogenesis process in the eye was analysed as well at similar time points as the retinal findings.

Results: After 12 months of treatment, the placebo group had a significant increase of 23.42% in retinal microhaemorrhages (p < 0.05), but the Tocovid group had no significant changes. Moreover, the Tocovid group showed a significant decrease of 48.38% in area of diabetic macular oedema over the 12 months period (p < 0.05), but the placebo group had no significant changes. Meanwhile, there was no significant difference in serum vascular endothelial growth factor level when comparing between both groups.

Conclusion: These findings could indicate that Tocovid has an important role in preventing early diabetic retinopathy progression.

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Effects of delta-tocotrienol supplementation on glycaemic control in individuals with prediabetes: A randomized controlled study

Farhana Suleman, Dilshad Ahmed Khan, Muhammad Amjad Pervez, Mohammad Aamir

J Pak Med Assoc . 2022 Jan;72(1):4-7. doi: 10.47391/JPMA.966.

Abstract

Objective: To study the effects of delta-tocotrienol on glycaemic control parameters in individuals with pre-diabetes.

Methods: The randomised control trial was conducted at the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from July 15 to November 15, 2019, and comprised individuals aged 18-60 years having fasting plasma glucose of 5.6 to 6.9 mmol/L or glycosylated haemoglobin of 5.7 to 6.4%. They were randomised into group A receiving 300mg delta-tocotrienol and group B receiving a placebo once daily for 12 weeks. Weight, height, waist circumference, fasting plasma glucose, insulin and glycosylated haemoglobin were measured at the beginning and end of the trial to assess any change. Body mass index and homeostatic model assessment-insulin resistance were also calculated. Data was analysed using SPSS 21.

Results: Of the 77participants, 40(52%) were in group A and 37(48%) in group B. Group A showed significantly greater reduction in terms of fasting plasma glucose, glycosylated haemoglobin, insulin and homeostatic model assessment-insulin resistance index (p≤0.001) post-intervention.

Conclusions: Delta-tocotrienol supplementation was found to have a significant effect in improving glycaemic control parameters in persons with pre-diabetes. Futures larger scale clinical trials are needed to confirm these findings.

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Tocotrienols-rich naringenin nanoemulgel for the management of diabetic wound: Fabrication, characterization and comparative in vitro evaluations

Eileen Yeo, Clement Jia Yew Chieng, Hira Choudhury, Manisha Pandey, Bapi Gorain

Curr Res Pharmacol Drug Discov . 2021 Mar 14;2:100019. doi: 10.1016/j.crphar.2021.100019. eCollection 2021.

Abstract

The present research had been attempted to formulate and characterize tocotrienols-rich naringenin nanoemulgel for topical application in chronic wound conditions associated with diabetes. In due course, different phases of the nanoemulsion were chosen based on the solubility study, where combination of Capryol 90 and tocotrienols, Solutol HS15, and Transcutol P were selected as oil, surfactant, and cosurfactant, respectively. The nanoemulsions were formulated using the spontaneous emulsification method. Subsequently, Carbopols were incorporated to develop corresponding nanoemulgels of the optimized nanoemulsions. Thermodynamically stable optimized nanoemulgels were evaluated for their globule size, polydispersity index (PDI), surface charge, viscosity, mucoadhesive property, spreadability, in vitro release and release mechanism. Further, increasing polymer concentration in the nanoemulgels was reflected with the increased mucoadhesive property with corresponding decrease in the release rate of the drug. The optimized nanoemulgel (NG1) consisted of uniform dispersion (PDI, 0.452 ​± ​0.03) of the nanometric globules (145.58 ​± ​12.5) of the dispersed phase, and negative surface charge (-21.1 ​± ​3.32 ​mV) with viscosity 297,600 ​cP and good spreadability. In vitro release of naringenin in phosphate buffer saline revealed a sustained release profile up to a maximum of 74.62 ​± ​4.54% from the formulated nanoemulgel (NG1) within the time-frame of 24 ​h. Alternatively, the release from the nanoemulsion was much higher (89.17 ​± ​2.87%), which might be due to lack of polymer coating on the dispersed oil droplets. Moreover, the in vitro release kinetics from the nanoemulgel followed the first-order release and Higuchi model with non-Fickian diffusion. Therefore, encouraging results in this research is evident in bringing a promising future in wound management, particularly associated with diabetes complications.

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Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial

Pei Fen Chuar, Yeek Tat Ng, Sonia Chew Wen Phang, Yan Yi Koay, J-Ian Ho, Loon Shin Ho, Nevein Philip Botross Henien, Badariah Ahmad, Khalid Abdul Kadir

Nutrients . 2021 Oct 25;13(11):3770. doi: 10.3390/nu13113770.

Abstract

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFβ-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

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Systematic review and meta-analyses of vitamin E (alpha-tocopherol) supplementation and blood lipid parameters in patients with diabetes mellitus

Abolfathi Mohammad, Ebrahim Falahi, Mohd Yusof Barakatun-Nisak, Zubaidah Nor Hanipah, S Mohd Redzwan, Loqman Mohamad Yusof, Mohsen Gheitasvand, Farahnaz Rezaie

Diabetes Metab Syndr . Jul-Aug 2021;15(4):102158. doi: 10.1016/j.dsx.2021.05.031. Epub 2021 May 31.

Abstract

Background and aims: The studies have shown that α-tocopherol supplementation could improve lipid profile in diabetes mellitus (DM) patients. Nonetheless, the result remains inconsistent. Therefore, this meta-analysis was performed to evaluate the efficacy of α-tocopherol supplement on lipid parameters in DM patients.

Methods: We conducted an extensive search via Cochrane Library, PubMed, Scopus, and Web of Science databases to acquire the reported RCTs up to October 2020.

Results: The results showed no effects of α-tocopherol supplementation on lipid profile in DM patients except when used ≥12 weeks.

Conclusions: α-tocopherol supplementation in DM patients had no significant effect on lipid profiles.

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Quercetin and vitamin E attenuate diabetes-induced testicular anomaly in Wistar rats via the mitochondrial-mediated apoptotic pathway

Oluwatoyin Osinimega Ojo, Olufunso Olabode Olorunsogo

Andrologia . 2021 Jul 18;e14185. doi: 10.1111/and.14185. Online ahead of print.

Abstract

The role of quercetin and vitamin E treatment against streptozotocin (STZ)-induced testicular abnormalities in diabetic rats and the possible mechanism of action they use for protection were investigated. Diabetes was induced by STZ (45 mg/kg i.p. once) and blood glucose was determined. Plasmatic insulin, testosterone, luteinising hormone and follicle-stimulating hormone (FSH) were determined by ELISA. Levels of cytochrome c, caspase 3 and caspase 9 were evaluated by immunohistochemistry, while lesions were viewed by histology. Insulin played a role in testicular protection against male infertility through modulation of luteinising hormone (LH). This consequently increased Leydig and Sertoli cells and maturation of germ cells with the attached epididymis having abundant spermatozoa. The study showed a positive correlation in the levels of LH, FSH and testosterone; it was further established that all treatments normalised diabetes-induced alterations. Treatment with quercetin and vitamin E resulted in 34% decrease of apoptogenic cytochrome c release. This protected the testes against excessive apoptosis by decreasing caspase 3 and caspase 9 activation by up to 30 and 28% respectively (p < .05). Histology also showed that treatment prevented testicular cell death. The findings show that quercetin/vitamin E possess free radical scavenging properties that protected against testicular damage in diabetes. This suggests the possibility of pharmaco-therapeutic intervention.

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Dehydro-Tocotrienol-β Counteracts Oxidative-Stress-Induced Diabetes Complications in db/db Mice

Gustav Dallner, Magnus Bentinger, Shafaat Hussain, Indranil Sinha, Jiangning Yang, Cheng Schwank-Xu, Xiaowei Zheng, Ewa Swiezewska, Kerstin Brismar, Ismael Valladolid-Acebes, Michael Tekle

Antioxidants (Basel) . 2021 Jul 2;10(7):1070. doi: 10.3390/antiox10071070.

Abstract

Hyperglycemia, hyperlipidemia, and adiposity are the main factors that cause inflammation in type 2 diabetes due to excessive ROS production, leading to late complications. To counteract the effects of increased free radical production, we searched for a compound with effective antioxidant properties that can induce coenzyme Q biosynthesis without affecting normal cellular functions. Tocotrienols are members of the vitamin E family, well-known as efficient antioxidants that are more effective than tocopherols. Deh-T3β is a modified form of the naturally occurring tocotrienol-β. The synthesis of this compound involves the sequential modification of geranylgeraniol. In this study, we investigated the effects of this compound in different experimental models of diabetes complications. Deh-T3β was found to possess multifaceted capacities. In addition to enhanced wound healing, deh-T3β improved kidney and liver functions, reduced liver steatosis, and improved heart recovery after ischemia and insulin sensitivity in adipose tissue in a mice model of type 2 diabetes. Deh-T3β exerts these positive effects in several organs of the diabetic mice without reducing the non-fasting blood glucose levels, suggesting that both its antioxidant properties and improvement in mitochondrial function are involved, which are central to reducing diabetes complications.

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Correlation between Levels of Vitamins D 3 and E in Type 2 Diabetes Mellitus: A Case-Control Study in Serdang, Selangor, Malaysia

Nurliyana Najwa Md Razip, Banulata Gopalsamy, Mohd Sokhini Abdul Mutalib, Sui Kiat Chang, Muhammad Mikhail Joseph Anthony Abdullah, Azrina Azlan, Zulida Rejali, Huzwah Khaza'ai

Nutrients . 2021 Jul 1;13(7):2288. doi: 10.3390/nu13072288.

Abstract

An overview of vitamins D3 and E suggests micronutrient deficiency contributes to type 2 diabetes mellitus (T2DM). A case-control study was conducted to determine the status of plasma vitamins D3 and E isomers amongst diabetic Malaysians. Two groups were recruited for participation, one comprising fifty diabetic subjects (DM) and one comprising fifty non-diabetic (non-DM) subjects, in order to assess their plasma vitamin D3, calcium and vitamin E status. Glycaemic status (haemoglobin A1c, HbA1c; fasting blood glucose, FBG; C-Peptide) and lipid profiles (total cholesterol, TC; triglycerides, TG; low-density lipoprotein-cholesterol, LDL-C; high-density lipoprotein-cholesterol, HDL-C) were assessed, followed by anthropometric measurements. The Mann-Whitney U-test, Kruskal-Wallis and Spearman’s correlation coefficient were used to elucidate the association between levels of plasma vitamins D3 and E and T2DM. The vitamin D3 deficiency group (<20 ng/mL) showed a significant correlation (p < 0.05) with glycaemic status (HbA1c and FBG) and lipid profiles (HDL-C, LDL and TC). Spearman’s correlation demonstrated that vitamin D3 status is strongly correlated with HDL levels (p < 0.05). Similarly, plasma total vitamin E levels >4.9 μg/mL revealed significantly different FBG, HbA1c, C-Peptide, LDL, HDL and TC levels across both groups. Moreover, family history, smoking, waist circumference and HbA1c levels demonstrated a significant association (p < 0.05) with levels of vitamins D and E but not FBG and lipid profiles. This could be because the pre-diabetic status among the non-DM group influenced the outcomes of this study.

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Effects of delta-tocotrienol supplementation on Glycemic Control, oxidative stress, inflammatory biomarkers and miRNA expression in type 2 diabetes mellitus: A randomized control trial

Wajiha Mahjabeen, Dilshad Ahmed Khan, Shakeel Ahmed Mirza, Muhammad Amjad Pervez

Phytother Res . 2021 Apr 25. doi: 10.1002/ptr.7113. Online ahead of print.

Abstract

The study aimed to ascertain the effects of delta-tocotrienol (δT3) supplementation on glycemic control, oxidative stress, inflammation and related micro-ribonucleic acid (miRNA) expression in patients with type 2 diabetes mellitus (T2DM). Total 110 patients of T2DM on oral hypoglycemic agents, were randomly divided into tocotrienol and placebo groups and given 250 mg δT3 or cellulose soft gel capsule once daily respectively for 24 weeks. Glycemic control, oxidative stress, inflammatory biomarkers, and miRNAs expression were measured in serum at baseline and end of the intervention by using standard laboratory methods. Compared to the placebo, δT3 supplementation resulted in a significant (p ≤ .05) reduction [mean difference (95% confidence interval)] in plasma glucose [-0.48 (-0.65, -0.30)], insulin [-1.19 (-1.51, -0.87)], homeostatic model assessment of insulin resistance [-0.67 (-0.86, -0.49)], glycosylated hemoglobin [-0.53 (-0.79, -0.28)], malondialdehyde [-0.34 (-0.45, -0.22)], high sensitive-C-reactive protein[-0.35 (-0.54, -0.16)], tumor necrosis factor-alpha [-1.22 (-1.62, -0.83)], and interleukin-6[-2.30 (-2.91, -1.68)]. More than twofold downregulation in miRNA-375, miRNA-34a, miRNA-21, and upregulation in miRNA-126, miRNA-132 expression was observed in the δT3 group compared to the placebo. The study demonstrated that δT3 supplementation in addition to oral hypoglycemic agents, improved glycemic control, inflammation, oxidative stress, and miRNA expression in T2DM without any adverse effect. Thus, δT3 might be considered as an effective dietary supplement to prevent long-term diabetic complications.

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The Combination of Berberine, Tocotrienols and Coffee Extracts Improves Metabolic Profile and Liver Steatosis by the Modulation of Gut Microbiota and Hepatic miR-122 and miR-34a Expression in Mice

Valentina Cossiga, Vincenzo Lembo, Cecilia Nigro, Paola Mirra, Claudia Miele, Valeria D'Argenio, Alessia Leone, Giovanna Mazzone, Iolanda Veneruso, Maria Guido, Francesco Beguinot, Nicola Caporaso, Filomena Morisco

Nutrients . 2021 Apr 13;13(4):1281. doi: 10.3390/nu13041281.

Abstract

Non-alcoholic-fatty liver disease (NAFLD) is spreading worldwide. Specific drugs for NAFLD are not yet available, even if some plant extracts show beneficial properties. We evaluated the effects of a combination, composed by Berberis Aristata, Elaeis Guineensis and Coffea Canephora, on the development of obesity, hepatic steatosis, insulin-resistance and on the modulation of hepatic microRNAs (miRNA) levels and microbiota composition in a mouse model of liver damage. C57BL/6 mice were fed with standard diet (SD, n = 8), high fat diet (HFD, n = 8) or HFD plus plant extracts (HFD+E, n = 8) for 24 weeks. Liver expression of miR-122 and miR-34a was evaluated by quantitativePCR. Microbiome analysis was performed on cecal content by 16S rRNA sequencing. HFD+E-mice showed lower body weight (p < 0.01), amelioration of insulin-sensitivity (p = 0.021), total cholesterol (p = 0.014), low-density-lipoprotein-cholesterol (p < 0.001), alanine-aminotransferase (p = 0.038) and hepatic steatosis compared to HFD-mice. While a decrease of hepatic miR-122 and increase of miR-34a were observed in HFD-mice compared to SD-mice, both these miRNAs had similar levels to SD-mice in HFD+E-mice. Moreover, a different microbial composition was found between SD- and HFD-mice, with a partial rescue of dysbiosis in HFD+E-mice. This combination of plant extracts had a beneficial effect on HFD-induced NAFLD by the modulation of miR-122, miR-34a and gut microbiome.

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