Other Metabolic Health

Published Human Studies / Cohort Studies

Article Study Objectives / Findings
The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetic Neuropathy: A Phase II Randomized Controlled Trial.

Ng, Y.T., et al., (2020). Nutrients

80 eligible participants were randomized into 2 groups; (i) receives 200mg EVNol SupraBio™, or, (ii) placebo, twice a day. The nerve conduction velocity test was carried out on 3 nerves – median, sural, and tibial; and a conduction velocity test measures how fast the nerves could send important signals. After 8 weeks of supplementation, the results showed that there was a highly significant improvement in nerve conduction velocities of all nerves in participants receiving tocotrienol. This study discovered that serum nerve growth factor (NGF) is significantly elevated among the participants on tocotrienol’s supplementation.
Tocotrienol-rich vitamin E improves diabetic nephropathy and persists 6–9 months after washout: a phase IIa randomized controlled trial.

Tan, G. C. J., et al., (2019). Ther. Adv. Endocrinol. Metab.

In this study, a total of 54 diabetic nephropathy patients were randomized into two groups; (i) receiving 200mg EVNol SupraBio™ twice daily, or, (ii) receiving placebo daily. After 12 weeks of supplementation of tocotrienol, the study discovered there was a significant decrease in serum creatinine resulting in an increase in eGFR. The patients in the placebo group showed a contrasting result. this study also discovered the patients in the tocotrienol group still had stable renal function (serum creatinine reading) even after cessation of tocotrienol for 6-9 months. 

Comparing the effects of vitamin E tocotrienol-rich fraction supplementation and α-tocopherol supplementation on gene expression in healthy older adults

Ghani, S.M.A., et al., (2019). Clinics

In this study, 71 volunteers were randomized into 3 groups receiving either placebo, alpha-tocopherol, or tocotrienol-rich fraction. Blood sampling was performed at baseline (month 0) and at 3 and 6 months of supplementation. The study observed that supplementation with either α-tocopherol or TRF modulated the immune system, response to drug, cell adhesion and signal transduction pathways. However, TRF supplementation showed a more pronounced effect than α-tocopherol in modulating the expression of genes in signalling pathways. The antioxidative and anti-inflammatory properties of TRF observed in female subjects may be attributed to the downregulation of the apoptotic pathway, ERK1/2 cascades and NF-kB pathway after 6 months of supplementation.

Tocotrienol-Rich Vitamin E from Palm Oil (Tocovid) and Its Effects in Diabetes and Diabetic Nephropathy: A Pilot Phase II Clinical Trial.

Tan, S., et al., (2018). Nutrients.

Diabetic nephropathy is one of the diabetes complications. In this study, 45 diabetic patients were randomized to receive either 200 mg mixed tocotrienols (EVNol SupraBio™) or placebo; twice daily. The serum creatinine (high level of creatinine is a sign of kidney damage) was measured. After 2 months of supplementation, it was observed that the serum creatinine in the EVNol SupraBio™ group decreased significantly. The other diabetic biomarkers, however, were not reduced. It is concluded that EVNol SupraBio™ supplementation may be a useful addition to the current treatment for diabetic nephropathy.
Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy: A Randomized Clinical Trial.

VENUS Investigators (2018). JAMA Neuro.

To evaluate the efficacy of oral mixed tocotrienols for patients with diabetic peripheral neuropathy, a total of 300 patients were randomly assigned into 2 groups: (1) receiving 200 mg mixed tocotrienols (EVNol SupraBio™ or (2) placebo; twice daily. Supplementation of oral mixed tocotrienols did not improve overall neuropathic symptoms. It is also observed that tocotrienol reduce lancinating pain.
Effect of palm-based tocotrienols and tocopherol mixture supplementation on platelet aggregation in subjects with metabolic syndrome: a randomised controlled trial.

Gan, Y. L., et. al., (2017). Scientific Reports.

This study was conducted to investigate the effect of palm-based tocotrienols and tocopherol mixture (EVNol SupraBio™) supplementation on platelet aggregation reactivity. The participants were supplemented with 200 mg twice daily of tocotrienol mixture or placebo capsules for 14 days in a random order. Blood samples were collected on day 0, day 14 and during postprandial for the measurement of platelet aggregation reactivity. The results of this study highlight the lack of inhibitory effect on platelet aggregation after short-term supplementation of tocotrienol mixture in participants with metabolic syndrome.
Short-term effects of a combined nutraceutical of insulin-sensitivity, lipid level and indexes of liver steatosis: a double blind, randomized, cross-over clinical trial.

Cicero, A.F., et.al (2015). Nutr J.

To evaluate the effect of a combined nutraceutical containing berberine, chlorogenic acid and tocotrienols, we performed a double blind, cross-over designed trial versus placebo, in 40 overweight subjects with mixed hyperlipidaemia. This combination seems to improve a large number of metabolic and liver parameters on the short-term in overweight subjects. Further studies are needed to confirm these observations on the middle- and long-term.
The Effects of Tocotrienols Added to Canola Oil on Microalbuminuria, Inflammation, and Nitrosative Stress in Patients with Type 2 Diabetes: A Randomized, Double-blind, Placebo-controlled Trial.

Haghighat, N., et.al (2014). Int J Prev Med.

Tocotrienols (T3) were neglected in the past; today, get attentions due to their antioxidant and none-antioxidant activity. The objective of this study was to evaluate the effects of the daily intake of 200 mg T3 added in canola oil over 8 weeks on microalbuminuria, inflammation, and nitrosative stress in type 2 diabetic patients. These findings indicate that T3 leads to ameliorate proteinuria and can protect the kidney against inflammation (hs-CRP) and nitrosative stress (NO).
The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia.

Baliarsingh, S., et.al (2005). Atherosclerosis.

The therapeutic impacts of tocotrienols on serum and lipoprotein lipid levels in type 2 diabetic patients were investigated. Daily intake of dietary TRF by type 2 diabetics will be useful in the prevention and treatment of hyperlipidemia and atherogenesis.
Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia

Mustard, V.A., et.al (2002). American Society for Clinical Nutrition.

The objective was to study the relative effect of tocotrienol supplements of different compositions (mixed α- plus γ-, high γ-, or P25-complex tocotrienol) on blood lipids, fasting blood glucose, and the excretion of 8-iso-prostaglandin F, a measure of oxidative stress, in healthy hypercholesterolemic men and women. Supplementation with 200 mg tocotrienols/d from 3 commercially available sources has no beneficial effect on key cardiovascular disease risk factors in highly compliant adults with elevated blood lipid concentrations.

In- vivo / Animal Studies


Article Study objective/ findings
Protective Effect of Palm Oil-Derived Tocotrienol-Rich Fraction Against Retinal Neurodegenerative Changes in Rats with Streptozotocin-Induced Diabetic Retinopathy.

Sadikan, M. Z., et al., (2020). Biomolecules

In the study, the diabetes-induced rats were divided into two treatment groups based on the route of administration of treatment — oral treatment group and topical treatment group. EVNol™ was given orally in a dose of 100 mg/kg body weight to rats in the oral treatment group (DTO). For topical application, 0.03% microemulsion formulation of EVNol™ was used in the topical treatment group (DTE). After 12 weeks of treatment, morphological and biochemical analysis on the rats’ eyeballs were conducted. in the oral EVNol™-treated group, the thickness of the retinal was significantly greater compared to the corresponding diabetic control groups of oral. A significantly greater retinal cell counts were also observed in the oral EVNol™-treated group.

Tocomin Restores Endothelium-Dependent Relaxation in the Diabetic Rat Aorta by Increasing NO Bioavailability and Improving the Expression of eNOS.

Ali, S.F., et al., (2019). Frontiers in Physiology

Palm tocotrienol-rich fraction, Tocomin (now known as EVNol™), was able to reduce O2- production and improve endothelium-dependent relaxation in rat aorta in the presence of chemically-induced oxidative stress. This study aimed to test the hypothesis that treatment with EVNol™ would preserve endothelial function in aortae isolated from type 1 diabetic rats. This study demonstrated that the in vivo treatment of diabetic rats with the tocotrienol-rich extract of palm oil; EVNol™, increased NO activity to improve endothelium-dependent relaxation. EVNol™ did not affect diabetes-induced hyperglycaemia or weight-loss but did attenuate the vascular oxidative stress in the aortae. EVNol™ also reduced O2- production in the diabetic aortae which was directly correlated with a decrease in Nox2 expression.
Effects of delta-tocotrienol on obesity-related adipocyte hypertrophy, inflammation and hepatic steatosis in high-fat-fed mice.

Allen, L., et.al., (2017). J Nutr Biochem.

It is hypothesized that delta-tocotrienol (δT3) reduces adiposity, insulin resistance and hepatic triglycerides through its anti-inflammatory properties. To test this hypothesis, C57BL/6J male mice were fed a high-fat diet (HF) with or without supplementation of δT3 (HF+δT3) at 400 mg/kg and 1600 mg/kg for 14 weeks, and they were compared to mice fed a low-fat diet (LF) or HF supplemented with metformin as an antidiabetic control. Glucose tolerance tests were administered 2 weeks prior to the end of treatments. Histology, quantitative polymerase chain reaction and protein analyses were performed to assess inflammation and fatty acid metabolism in adipose and liver tissues. Significant improvements in glucose tolerance, and reduced hepatic steatosis and serum triglycerides were observed in δT3-supplemented groups compared to the HF group. Body and fat pad weights were not significantly reduced in HF+δT3 groups; however, we observed smaller fat cell size and reduced macrophage infiltration in their adipose tissues compared to other groups. These changes were at least in part mechanistically explained by a reduction of mRNA and protein expression of proinflammatory adipokines and increased expression of anti-inflammatory adipokines in HF+δT3 mice. Moreover, δT3 dose-dependently increased markers of fatty acid oxidation and reduced markers of fatty acid synthesis in adipose tissue and liver. In conclusion, our studies suggest that δT3 may promote metabolically healthy obesity by reducing fat cell hypertrophy and decreasing inflammation in both liver and adipose tissue.
Tocotrienols Stimulate Insulin Secretion of Rat Pancreatic Isolated Islets in a Dynamic Culture.

Chia, L.L, et.al (2017). Curr Pharm Biotechnol.

 The objective of this study was to determine the effects of T3 derivatives, δ-T3, γ-T3 and α-T3 on insulin secretion of rat pancreatic islets in a dynamic culture.The findings suggest the potential of δ-T3 in regulating glucose-stimulated insulin secretion (GSIS) in response to the intracellular calcium especially in the presence of KCl.
Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats.

Wong, W.Y., et.al (2017). Eur J Nutr.


This study tested the hypothesis that γ- and δ-tocotrienols are more effective than α-tocotrienol and α-tocopherol in attenuating the signs of diet-induced metabolic syndrome in rats. In rats, δ-tocotrienol improved inflammation, heart structure and function, and liver structure and function, while γ-tocotrienol produced more modest improvements, with minimal changes with α-tocotrienol and α-tocopherol. The most important mechanism of action is likely to be reduction in organ inflammation. 
Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice.

Shin, J., et.al (2017). Exp Biol Med (Maywood).

This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1.
Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats.

Abdul N. N.A., et.al (2017). PLoS One.

In current study, we investigated anticataract effects of topical tocotrienol and possible mechanisms involved in streptozotocin-induced diabetic rats. In conclusion, preventive effect of topical tocotrienol on development of cataract in STZ-induced diabetic rats could be attributed to reduced lens aldose reductase activity, polyol levels and oxidative-nitrosative stress. These effects of tocotrienol invlove reduced NFκB activation, lower iNOS expression, restoration of ATP level, ATPase activities, calpain activity and lens protein levels.
Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes.

Kim, Y., et.al (2016). J Lipid Res.

The effects of γT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. γT3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of γT3. Collectively, it is demonstrated that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases.
Gamma-tocotrienol attenuates high-fat diet-induced obesity and insulin resistance by inhibiting adipose inflammation and M1 macrophage recruitment.

Zhao, L, et.al (2015). Int J Obes (Lond)

In this study, our objective was to investigate the γT3 effects on early-onset obesity, inflammation and insulin resistance in vivo. Our results demonstrated that γT3 ameliorates HF diet-mediated obesity and insulin resistance by inhibiting systemic and adipose inflammation, as well as ATM recruitment.
Tocotrienols have a nephroprotective action against lipid-induced chronic renal dysfunction in rats.

Rashid, K.M., et.al (2014). Ren Fail.

This study was conducted to determine if T3 as tocotrienol-rich fraction (TRF) from palm oil would protect against lipid-induced CRD in rats. For the induction of atherosclerosis and hyperlipidemia, Wistar male rats were fed an atherogenic diet containing 1.25% cholesterol, 0.5% cholic acid and 21% beef tallow (42.6% calories from fat). These findings show that low-dose treatment of TRF may provide significant health benefits in the prevention of lipid-induced CRD. The study suggests that TRF is effective in preventing lipid-induced CRD.
Tocotrienols Reverse Cardiovascular, Metabolic and Liver Changes in High Carbohydrate, High Fat Diet-Fed Rats.

Wong, W-Y., et.al (2012). Nutrients.

The effects of palm tocotrienol-rich fraction (TRF) on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats were investigated. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome. 
Effect of palm oil (Elaeis guineensis) tocotrienols on mesenteric adipose tissue deposition and the expression of 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1) in adrenalectomized rats treated with dexamethasone.

Azwan, K, et.al (2015). Clin Ter.

A study was done to investigate the effect of palm oil (Elaeis guineensis) tocotrienols on (1) rats mesenteric adipose tissue deposition (2) and 11β-HSD1 enzyme expression in mesenteric adipocyte. There is a necessity to find an inhibitor for the 11β-HSD1 enzyme which enhances the proliferation of mesenteric adipocyte tissue therefore curbing the onset of metabolic syndrome. This study suggests palm tocotrienol inhibits 11β-HSD1 enzyme expression and activity.

In vitro Studies

Article Study Objectives/ Findings

Mono-epoxy-tocotrienol-α enhances wound healing in diabetic mice and stimulates in vitro angiogenesis and cell migration.

Xu, C. et.al (2017). J Diabetes Complications

The effects of mono-epoxy-tocotrienol-α on in vitro and in vivo wound healing models as well as its effects on mitochondrial function are investigated. In vitro, significant increase in wound closure and cell migration both in normal and high glucose and in endothelial tube formation (angiogenesis) were observed. Microarray profiling analysis showed a 20-fold increase of KIF26A gene expression and 11-fold decrease of lanosterol synthase expression. Expression analysis by qPCR showed significant increase of the growth factors VEGFA and PDGFB. The epoxidated compound induced a significantly higher basal and reserve mitochondrial capacity in both HDF and HepG2 cells. Additionally, in vivo wound healing in db/db mice, demonstrated a small but significant enhancement on wound healing upon local application of the compound compared to treatment with vehicle alone. Mono-epoxy-tocotrienol-α seems to possess beneficial effects on wound healing by increasing the expression of genes involved in cell growth, motility and angiogenes as well as on mitochondrial function.
Differentiation and apoptosis induction by lovastatin and γ-tocotrienol in HL-60 cells via Ras/ERK/NF-κB and Ras/Akt/NF-κB signaling dependent down-regulation of glyoxalase 1 and HMG-CoA reductase.

Chen, C.C., et.al (2015). Cell Signal.

Glyoxalase 1 (GLO1) and HMG-CoA reductase (HMGCR) are highly expressed in most tumor cells and little in normal cells. In this study, treatment of HL-60 cells with lovastatin induced characteristic apoptosis in a dose-dependent manner. We demonstrated that lovastatin treatment inhibited Ras and Raf protein translocation to cell membrane and eliminated the phosphorylation of the downstream effectors Akt and ERK, and the subsequent NF-κB translocation into nucleus. Specific inhibitors and γ-tocotrienol confirmed the Ras/Raf/ERK/NF-κB/GLO1 and Ras/Akt/NF-κB/GLO1 pathways. Data revealed that lovastatin induced HL-60 cell death was attenuated by mevalonate treatment. We demonstrated also that γ-tocotrienol showed its apoptotic effect on the HL-60 cell through the same pathway. γ-Tocotrienol enhanced the apoptotic effect of lovastatin through the down-regulation of GLO1 and HMGCR resulting in an increase of methylglyoxal and a decrease of cholesterol and led to the apoptosis of HL-60 cells. Data also revealed that both lovastatin and gamma-tocotrienol induced significant HL-60 cell differentiation. These results suggest that both lovastatin and gamma-tocotrienol could induce differentiation and followed by apoptosis.
Tocotrienol modulates crucial lipid metabolism-related genes in differentiated 3T3-L1 preadipocytes.

Burdeos, G.C., et.al (2014). Food Funct.

In this study, a series of fascinating experimental findings on how T3 affects lipid metabolism in differentiated 3T3-L1 preadipocytes. Treatment with T3 (25 μM), especially δ and γ isomers, inhibited the accumulation of triglyceride and lipid droplets in differentiated 3T3-L1 cells is reported. This manifestation was supported by mRNA and protein expression of crucial lipid metabolism-related genes. The present study provides a novel set of data pertaining to the possibility of T3 as an anti-metabolic disorder agent.

Review Article

Article Study Objectives/ Findings
The Role of Tocotrienol in Protecting Against Metabolic Diseases

Pang, K. L., & Chin, K. Y. (2019). Molecules

Obesity is a major risk factor for diabetes, and these two metabolic conditions cause a significant healthcare burden worldwide. This review summarized the current evidence on the anti-obesity and antidiabetic effects of tocotrienol. The evidence accumulated so far, mostly preclinical, supports the therapeutic role of high doses of T3 in preventing or reversing obesity and diabetes, and their multisystemic complications. However, more studies are warranted before it can be used clinically in the management of obesity and diabetes.
The Molecular Mechanism of Vitamin E as a Bone-Protecting Agent: A Review on Current Evidence

Wong, S.K., et.al (2019). Int. J. Mol. Sci.

Vitamin E has been extensively reported for its anti-osteoporotic properties using various male and female animal models. This review summarized the evidence elucidating the mechanism and molecular action of Vitamin E in bone remodelling.
Vitamin E As a Potential Interventional Treatment for Metabolic Syndrome: Evidence from Animal and Human Studies.

Wong, S.K., et.al (2017). Front Pharmacol.

 A constellation of medical conditions inclusive of central obesity, hyperglycemia, hypertension, and dyslipidemia is known as metabolic syndrome (MetS). The safest option in curtailing the progression of MetS is through maintaining a healthy lifestyle, which by itself, is a long-term commitment entailing much determination. A combination of pharmacological and non-pharmacological approach, as well as lifestyle modification is a more holistic alternative in the management of MetS. Vitamin E has been revealed to possess anti-oxidative, anti-inflammatory, anti-obesity, anti-hyperglycemic, anti-hypertensive and anti-hypercholesterolemic properties. The pathways regulated by vitamin E are critical in the development of MetS and its components. Therefore, we postulate that vitamin E may exert some health benefits on MetS patients. This review intends to summarize the evidence in animal and human studies on the effects of vitamin E and articulate the contrasting potential of tocopherol (TF) and tocotrienol (T3) in preventing the medical conditions associated with MetS. As a conclusion, this review suggests that vitamin E may be a promising agent for attenuating MetS.
Tocotrienol and its role in chronic diseases.

Chin, K.Y., et.al (2016). Adv Exp Med Biol.

This review aimed to discuss the health beneficial effects of tocotrienol, specifically in preventing or treating hyperlipidaemia, diabetes mellitus, osteoporosis and cancer with respect to these properties. Evidence from in vitro, in vivo and human studies has been examined. It is revealed that tocotrienol shows promising effects in preventing or treating the health conditions previously mentioned in in vivo and in vitro models. In some cases, alpha-tocopherol attenuates the biological activity of tocotrienol. Except for its cholesterol-lowering effects, data on the health-promoting effects of tocotrienol in human are limited. As a conclusion, the encouraging results on the health beneficial effects of tocotrienol should motivate researchers to explore its potential use in human.