Diabetes is a widespread disease all over the globe. The number of people suffering from diabetes has risen from 108 million in 1980 to 422 million in 2014 and the global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to around 8.5% in 2014. In 2016, around 1.6 million deaths were directly caused by diabetes while Another 2.2 million deaths were attributable to high blood glucose in 2012 Almost half of all deaths attributable to high blood glucose have occurred before the age of 70 years and according to WHO, diabetes was the 7th leading cause of death in 2016. Moreover, Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation.

With more than 62 million diabetic individuals currently diagnosed with this disease, in India itself, diabetes is fast gaining the status of a potential epidemic! In 2000, India with 31.7 million people affected from diabetes topped the world with the highest number of people with diabetes mellitus followed by China with 20.8 million of its population suffering and with the United States with 17.7 million in the second and third place respectively. The prevalence of diabetes is predicted to double globally from 171 million in 2000 to around 366 million by 2030 with the maximum increase in cases in India. It is estimated that by 2030, diabetes mellitus may rise up to 79.4 million individuals in India, while China (42.3 million) and the United States (30.3 million) will also see significant increases in those affected by the disease.

About 10% of the population of the United States of America has diabetes but to fight this deadly disease, researchers have discovered Tocotrienol (Eannatto – DeltaGold) and hence by learning more about how Tocotrienol (Eannatto – DeltaGold) can help lower the risk factor and/or manage this disease is very much important. Keeping in mind the importance of Tocotrienol (Eannatto – DeltaGold) against this disease, several studies have been conducted. Several studies have been highlighted under, “The Role of Tocotrienol in Protecting Against Metabolic Diseases”, have shown the anti-diabetic properties of Tocotrienol in cell lines, diabetic animals and humans studies and also effects of Tocotrienol (Eannatto – DeltaGold) in Diabetes – mediated lipid abnormalities, anti – inflammatory effects of Tocotrienol (Eannatto – DeltaGold) in Diabetic Models and so on.

Most research in the past 50 – 60 years has been focused on Tocopherols and 50% of all the research in last 30 years has been done on Tocotrienols in last 5 years. Half of the Tocotrienol research ever published has been published in last 10 years as shown in Fig. 1. Each day it is becoming increasingly understood that Tocotienols (especially Eannatto – DeltaGold) are the right form of Vitamin E. Well in excess of 100 studies and clinical trials have shown the surprising benefits of Tocotrienols – without any known side effects.

Fig. 1: In the graph, as you can see, R & D on Tocotrienol has increased exponentially over the years in all fields while research on Tocopherols has decreased. Whether it is cancer, Cardiovascular diseases (CVD), Diabetes, Anti – Oxidant activities or others, in all fields research on Tocotrienol has not only gained pace but quant as well.

Study 1 – Anti – diabetic Properties of Tocotrienol in Cell Lines and Diabetic Animals.

A multitude of animal studies demonstrated the anti – diabetic properties of Tocotrienol (Eannatto – DeltaGold), especially Gamma – Tocotrienol (Eannatto – DeltaGold) and Delta – Tocotrienol (Eannatto – DeltaGold), by preventing diabetic weight loss, hyperphagia, and polydipsia in type-1 diabetes mellitus (T1DM) and T2DM models. Besides, Tocotrienol (Eannatto – DeltaGold) (individual isoform or Tocotrienol Rich Fraction) significantly improved the glycemic status of diabetic animals by reducing blood glucose level and HbA1c level. Moreover, the combination treatment of Tocotrienol Rich Fraction and insulin resulted in better glycemic control in T1DM rats as compared to single treatment.

Mechanistically, Tocotrienol (Eannatto – DeltaGold) improved glycemic control in diabetic animals by improving insulin synthesis (insulin-tropic activity) and by enhancing insulin sensitivity. Chia et al. reported that Tocotrienol isoforms, including Alpha –Tocotrienol, Gamma – Tocotrienol (Eannatto – DeltaGold), and Delta – Tocotrienol (Eannatto – DeltaGold), demonstrated insulinotropic activities. Delta – Tocotrienol (Eannatto – DeltaGold) is the most potent isoform with insulinotropic activities, followed by Gamma – Tocotrienol (Eannatto – DeltaGold) and Alpha –Tocotrienol. Insulin releases genes, including insulin 1 (INS-1) and glucose transporter type-2 (GLUT2), and insulin gene transcription factors (MafA, PDX1, and BETA2), were up-regulated in Tocotrienol isoform-treated glucose-stimulated primary normal rat pancreatic β-islet cells. Moreover, co-treatment of Tocotrienol isoforms with potassium chloride further enhanced the INS-1 gene expression. Another similar study by Lee et al. also reported the insulinotropic activities of Gamma – Tocotrienol (Eannatto – DeltaGold) (1g/kg diet), whereby Gamma – Tocotrienol (Eannatto – DeltaGold) significantly suppressed the progression of diabetes in BKS.Cg-Dock7m+/+ Leprdb/J mice (db/db mice) by reducing the fasting blood glucose level and increasing adiponectin level. Besides, Gamma – Tocotrienol (Eannatto – DeltaGold) also enhanced the clearance of intraperitoneally injected glucose with a 2-fold increase of plasma insulin level in diabetic db/db mice. The histological analysis further revealed that Gamma – Tocotrienol (Eannatto – DeltaGold) attenuated the loss of pancreatic β-cells and delayed the progression of diabetes in db/db mice by increasing the average islet size, size distribution, and insulin-positive area with a lower degree of immune cell infiltration.

Another study from Fang et al. reported that TRF diet (50 mg/kg) improved insulin sensitivity by up-regulating PPAR and uncoupling protein 3 (UCP3) mRNA level in the muscles of non-fasting T1DM male C57BLKS/J-Lepr Db/Db mice. PPARα was potently activated upon TRF treatment, followed by PPARγ and PPARδ. In addition, purified Alpha –Tocotrienol and Gamma – Tocotrienol (Eannatto – DeltaGold) were observed to serve as a PPARα-selective agonist by activating PPARα. Purified Delta – Tocotrienol (Eannatto – DeltaGold), on the other hand, served as pan-PPAR agonist where it greatly activated PPARα and partially activated PPARγ and PPARδ. Furthermore, the molecular analysis also revealed that Alpha –Tocotrienol, Gamma – Tocotrienol (Eannatto – DeltaGold), and Delta – Tocotrienol (Eannatto – DeltaGold) served as direct PPARα agonist by enhancing the interaction between PPARα and PPARγ coactivator-1α (PGC-1α) in a dose-dependent manner. Parallel with the reporter assay, Delta – Tocotrienol (Eannatto – DeltaGold) also demonstrated a greater potency in enhancing PPARα-PGC-1α interaction as compared to other isoforms of Vitamin E. Molecular docking analysis also demonstrated that Delta – Tocotrienol (Eannatto – DeltaGold) exhibited higher affinity and formed greater H-bonding interaction with PPARδ and PPARγ as compared to Alpha –Tocotrienol, thus explaining its pan-PPAR agonist properties. In addition, Alpha –Tocotrienol, Gamma – Tocotrienol (Eannatto – DeltaGold), and Delta – Tocotrienol (Eannatto – DeltaGold) were also reported to up-regulate PPARδ and PPARγ mRNA level in glucose-stimulated primary pancreatic β-islet cells in normal rats.

Study 2 – Antidiabetic Activities of Tocotrienol in Human Studies

The Finnish Mobile Health Examination Survey, was conducted to inpect the relation between dietary intake of Tocotrienol isoforms and the risk of T2DM in 2285 men and 2019 women aged around 40–69 years and free from diabetes at baseline. It was observed that intake of Tocotrienol was significantly associated with the lower risk of T2DM.

Several studies showed that supplementation of Tocotrienol resulted in better glycemic control on diabetes patients. Tocotrienol – enriched canola oil (200 mg/day) supplied to 45 T2DM patients was demonstrated to reduce their fasting blood glucose level. The randomized controlled trial (RCT) of Vitamin E in Neuroprotection Study (VENUS) was conducted from 2011 until 2015 to identify the effects of Tocotrienol on glycemic control and neuroprotection. Among the 229 diabetic patients who completed this trial, oral supplementation of mixed Tocotrienol (400 mg/day) for 1 year was shown to improve their glycemic control. The dose of 400 mg T3 per day was considered safe for a human with no observed adverse effect.

Wan Nazaimoon et al. supplemented 32 T1DM patients with 1800 mg of a Tocotrienol – rich extract, Palmvitee (4% tocopherol and 16% T3 or equivalent to 288 mg T3) or refined palm oil (<0.1% T3) capsules daily for 60 days, followed by a washout period of 60 days and crossed over the treatment for another 60 days. The result showed that both Palmvitee and refined palm oil did not improve the glycemic status of T1DM patients with plateau HbA1c levels. Similarly, a double – blinded and placebo –controlled RCT was conducted on 19 T2DM patients with hyperlipidemia. The subjects received either placebo or a TRF treatment (6 mg/kg body mass/day for 60 days) comprising of 14.6% α-T3, 2.2% β-T3, 38.8% γ-T3, and 2.4% unidentified Tocotrienol. The result showed that TRF (due to presence of Tocopherol) did not significantly alter the fasting and postprandial glucose level, as well as the glycated hemoglobin level in these T2DM patients. In another RCT, TRF from palm oil (24.5% α-T3, 3.5% β-T3, 35.4% γ-T3, 12.7% δ-T3, and 23.9% Alpha-tocopherol) was orally administrated (552 mg/day) to 86 T2DM patients for 8 weeks. It also did not improve the glycemic status of these patients because the HbA1c, serum insulin, plasma glucose levels, and HOMA-IR values were unchanged (also due to presence of Tocopherol).

Study 3 – Effects of Tocotrienol in Diabetes-Mediated Lipid Abnormalities.t Here

Hyperglycemia in T2DM is often related with increased risk of hyperlipidemia, hyper – cholesterolaemia, hyper – triglyceridemia, and hyper – insulinemia. These lipid abnormalities are quite prevalent in diabetes patients due to insulin resistance or alteration of lipid metabolism pathway. Several studies reported that Tocotrienol (Eannatto – DeltaGold) reduced lipid abnormalities in diabetic animals. TRF from palm oil (200 mg/kg bw/day) and RBO (400 mg/kg bw/day) were observed to improve lipid profile by restoring the serum high – density lipoprotein cholesterol (HDL-C) level and suppressing the increased serum TC, TG, low-density lipoprotein cholesterol (LDL-C), and very low – density lipoprotein cholesterol (VLDL-C) levels in diabetic rats. Besides, low dose of Gamma – Tocotrienol (Eannatto – DeltaGold) (0.6 mg/g) in the RBO diet also significantly suppressed hyperlipidemia via reduction of plasma and hepatic TG and LDL-C levels in STZ – induced T2DM rats. Another similar study from Chou et al. demonstrated that high dose of Gamma – Tocotrienol (Eannatto – DeltaGold) (6 mg/g) in RBO diet also increased HDL-C level and reduced nonesterified fatty acid, liver cholesterol, and TC to HDL-C ratio in T2DM rats.

TRF was demonstrated to reduce serum total lipids, TC, and LDL-C levels of 19 T2DM patients with hyperlipidemia in one randomized, double-blinded and placebo-controlled trial. However, TRF did not alter the levels of VLDL-C, HDL-C, and TG in these T2DM patients. From human studies, T3-rich extract, Palmvitee (1800 mg/day) was administrated to 32 T1DM patients.

Study 4 – Anti-Inflammatory Effects of T3 in Diabetic Models

TRF was shown to normalize the inflammation-related markers including NF-κB, MCP-1, IL-6, and TNF-α in the skeletal muscle of STZ-induced diabetic C57BL/6J mice. Besides, Gamma – Tocotrienol (Eannatto – DeltaGold) was demonstrated to inhibit the downstream activation of caspase-1 and the release of IL-1β and IL-18 in isolated peritoneal macrophages from diabetic db/db mice upon stimulation of palmitate (inflammasome activator) and LPS. A similar finding was reported on Gamma – Tocotrienol (Eannatto – DeltaGold) -treated nigericin (inflammasome activator) and LPS-stimulated iJ774 macrophages and primary bone marrow – derived macrophages (BMDMs) from C57BL/6 mice. Mechanistically, suppression of caspase-1 activation and IL-1β secretion by Gamma – Tocotrienol (Eannatto – DeltaGold) were found to be dependent on nucleotide – binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome suppression but independent on A20 (a negative regulator of NF-κB).

Study 5 – Effects of T3 in Diabetes-Related Cardiovascular Diseases

TRF treatment (200 mg/kg bw/day) was reported to protect the thoracic aorta from diabetes-mediated vascular wall alterations in STZ-induced diabetic rats with a significant improvement of redox status. Biochemical and histological examination further revealed that TRF also suppressed the vascular smooth muscle cell degeneration in the aorta and inhibited the formation of electron-dense amorphous material in the aortic media.


Why Tocotrienol?

Fig. 2: In the study conducted by Dr. Qureshi, he saw that at 250 mg of Tocotrienols, the endogenous anti-oxidant, TAS (represented with grey colour) increased, while the C-reactive protein (CRP) dropped by 40%, oxidized fat (MDA) dropped by 34% and Total Anti-oxidant increased by 22%.
Fig. 3: In a Japanese study, it was observed that when Alpha-Tocopherol was used, no change was observed towards the treatment of Atherosclerosis but when it was treated with 0.2% Delta-Tocotrienol, there was a 24% decrease in Atherosclerotic Lesion.
Fig. 4: In a Malaysian study, the inflammation marker was observed to drop at both established period of plaque and early period of plaque formation in arteries. Adhesion molecules like Vasco – cellular adhesion molecules (VCAM), Intra – cellular adhesion molecules (ICAM) etc. cling on to the arterial walls and bring on microphages and cholesterol and form plaque but Tocotrienols were observed to inhibit adhesion molecules thus preventing plaque formation. Proteolytic enzymes which also encourage plaque formation were also observed to be reduced.


Why Tocotrienol and not Tocopherol?

Fig. 7: When a 275 mg/day of dose of Tocotrienol was given with 33% Alpha – Tocopherol for 48 months, it was observed that only 14% LDL was decreased while there was no change in Triglycerides. When a 200 mg/day of dose of Tocotrienol was given with 33% Alpha – Tocopherol for 1.5 months, it was observed that there was no change in either LDL or Triglycerides. When a 100 mg/day of dose of Tocotrienol was given with less than 10% of Alpha – Tocopherol for 1 month, it was observed that LDL decreased by 20% and Triglycerides decreased by 8%. When a 100 mg/day of dose of Tocotrienol was given with 0% of Alpha – Tocopherol for 1 month, it was observed that LDL decreased by 20% and Triglycerides decreased by 15% and when a 75 mg/day of dose of Tocotrienol was given with 0% of Alpha – Tocopherol for 2 months, it was observed that LDL decreased by 15% and Triglycerides decreased by 20%.
Fig. 8: The 2nd pie chart represents Palm Tocotrienol rich fraction with 32% Alpha – Tocopherol which was given to people and when the Alpha – Tocopherol was removed then it was represented by the 1st pie chart with 0.3% Alpha – Tocopherol which was then given to people. In the graph, the hollow bar represents the Tocotrienol with Tocopherol which reduced the concentrations of Alpha, Gamma and Delta Tocotrienol in the body but when Tocopherol was removed from the dosage (Solid grey bars in graph), the concentrations of Alpha, Gamma and Delta – Tocotrienol significantly increased.