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.
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.
- Antioxidants, especially Tocotrienol was observed to exhibit activity against diabetes by lowering inflammation and oxidative stress as shown in Fig. 2.
- Cholesterol reduction is a significant feature of Tocotrienols by suppression of HMGR (3-hydroxy3methyl-glutaryl-CoA reductase) the enzyme/protein responsible for the body’s cholesterol production.
- Cytokines associated with cardiovascular diseases were down-regulated by Tocotrienols according to the study done at the University of Missouri – Kansas City.
- PPAR alpha has been shown to be activated by Tocotrienols, which helps control the genes that are involved with burning fatty acids for fuel. PPAR alpha activated by Tocotrienols also improved blood glucose and insulin sensitivity. These are important aspects of metabolism for lowering triglycerides and raising blood sugar metabolism.
- Gamma – Tocotrienol and Delta – Tocotreinols are effective for lowering triglycerides and raising blood sugar metabolism.
- ‘Velcro effect” or Chemotaxis a process which initiates plaque formation in arterial walls and Atherosclerotic Lesion have also been observed to be reduced by Tocotrienol as shown in Fig. 3 and Fig. 4.
- Lipid peroxides in blood vessels and blood pressure have been observed to be lowered by Tocotrienols which improves total anti-oxidant status thus preventing hypertension.
- Carotid Arteriosclerosis has been observed to be reduced by Tocotrienol in several studies.
- Anti-inflammation are characteristic properties of Tocotrienols.
- Scientists from the Universityof Missouri – Kansas City report that Tocotrienol doses ranging from 125 – 750 mg/day combined with the healthy diet decreased lipids.
- Substances that complement Tocotrienol for high lipids include CoQ10, Omega – 3 fatty acids, Glucosomine, Chondroitin.
- Substances that complement Tocotrienol for Cardiovascular diseases and MetS include CoQ10, Omega – 3 fatty acids, Magnesium, Resveratrol, Red Yeast Rice, MK4, MK7.
Why Tocotrienol and not Tocopherol?
- Ineffective Tocopherol: Large clinical studies on alpha-tocopherol have shown it to be ineffective and possibly harmful. Also, Tocopherols do not have the cholesterol-lowering ability which Tocotrienols do.
- The inability of Tocopherol to regulate Cholesterol Synthesis: While Tocopherol has antioxidant value, they lack the ability to regulate cholesterol synthesis.
- Structure of Tocotrienol: Tocotrienol has a smaller structure and less molecular weight which helps it to move freely through the cell membranes to cover larger areas for added protection.
- Tocopherol, the enemy of Tocotrienol: Alpha-tocopherol has been observed to attenuate or interfere with the cholesterol-lowering function of Tocotrienols. Preparations effective in cholesterol-lowering action consist of 15% or less of alpha-tocopherol and 60% or more gamma and delta Tocotrienols while ineffective preparations consist of 20% or more alpha-tocopherol and 45% or less of gamma and delta-tocotrienols.
- Absorption: As compared to Tocopherols, Tocotrienols absorb better in the body and Tocopherols have been observed to prevent absorption of Tocotrienols.
- The Role of Tocotrienol in Protecting Against Metabolic Diseases by Kok-Lun Pang and Kok-Yong Chin.
- World Health Organisation (WHO): Diabetes
- Tocotrienols: Vitamin E for Cardiovascular benefits after all by Barrie Tan, Ph.D., and Anne M. Trias, MS.
- The Truth About Vitamin E: The Secret to Thriving with Annatto Tocotrienols by Barrie Tan