insulin

Vitamin E

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Introduction

Vitamin E was the fifth vitamin discovered and hence its name. The existence of vitamin E was first recognized in 1922. It was observed that female rats required a previously unknown dietary factor to maintain pregnancies. Deficient females would ovulate and conceive properly; however, at some point in the pregnancy a spontaneous miscarriage would occur; additionally, lesions in the male’s testes were reported.

It has been estimated that by simply taking just 100 IU of vitamin E daily for those over 50 could save 5-6 billion dollars (source). Vitamin E is a fat-soluble nutrient that has eight active and naturally occurring plant constituents called tocopherols and tocotrienols. The various forms of vitamin E have overlapping and subtle biologic activities. Tocotrienols are less critical for biological physiology than tocopherols. Though tocotrienols have higher antioxidant activity than tocopherols, they have lower bioavailability following oral consumption.

In comparison to alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-) tocopherols are less biologically active. Various studies indicate that the body, through specific mechanisms prefers the accumulation of α-tocopherol after absorption. Vitamin E is found in various foods such as seeds and grains. However, the consumption of polyunsaturated fatty acids (PUFA's) increase the need for vitamin E (source, source, source). Vitamin E enhances vitamin A utilisation and functions as an antioxidant and antiestrogenic compound. At high doses, it inhibits platelet aggregation. Vitamin E and other nutrients may have protective effects against cancer, cardiovascular disease, diabetes and cataracts. Serum γ- and α-tocopherol concentrations are highly correlated with serum cholesterol and triglycerides (source, source).

Mechanism of Action

Vitamin E has a critical antiestrogenic (source, source), antioxidant (source)and cell signalling (source) activities. Tocopherols and tocotrienols are part of an interlinking set of antioxidant cycles which form an antioxidant network (source, source). Vitamin E acts directly on many oxygen radicals such as singlet oxygen, lipid peroxide products and superoxide radicals to form the relatively harmless tocopherol radical, protecting from lipid peroxidation (source). α-tocopherol can perform either as an antioxidant or as a prooxidant to promote the lipid peroxidation of LDL. Some have suggested that vitamin E may only be effective alongside vitamin C because it has been shown that the prooxidant activity of α-tocopherol is inhibited by ascorbate which acts as a co-antioxidant (source). Vitamin E also functions in conjunction with the trace element selenium, a cofactor for glutathione peroxidase, and other enzymes such as superoxide dismutase and catalase.

Through its ability to modulate platelet aggregation, α-tocopherol has been shown to play a crucial role in influencing the atherosclerotic process, endothelial dysfunction and inhibiting the activity of protein kinase C, an essential player in several signal transduction pathways (source). The antioxidant effect of vitamin E on LDL potentially retards atherosclerosis. In addition to its protection of nitric oxide, its inhibition of smooth muscle cell proliferation, its inhibition of adhesion to vascular endothelium of monocytes, platelets including other cells, and its modifications of eicosanoid production by neutrophils and monocytes (source). Due to its anti-inflammatory effect, vitamin E may protect against the progression of atherosclerosis. Vitamin E decreases the release of reactive oxygen species (ROS) and reduces lipid peroxidation, moreover, it reduces cytokines such as interleukin-1ss (IL-1ss) and tumour necrosis factor-alpha (TNF-α) along with decrease the adhesion of monocytes to human endothelium in doses of 1,200 IU daily (source). By inhibiting the activation of protein kinase C activity and nuclear factor-kappa B (NF-kappa B) vitamin E prevents leukocyte-endothelial cell adhesion by inhibiting signal transduction involved in the surface expression of adhesion molecules of leukocytes and endothelial cells (source), protecting from inflammation and atherosclerosis. Vitamin E supplementation has also been shown to improve endothelial-dependant vasodilation (source).

The form of vitamin E dictates its biological functions. α-tocopherol is the more effective chain breaking antioxidant for halting lipid peroxidation, while γ-tocopherol is much more effective at to trap lipophilic electrophiles like reactive nitrogen oxide species (source). Both α-tocopherol and γ-tocopherol can prevent smooth muscle cell proliferation by inhibiting the activity of protein kinase C. However, only γ-tocopherol and its metabolites which are water-soluble inhibit cyclooxygenase-2 (COX-2) activity in intact cells and capable of blocking the synthesis of prostaglandin E2 in lipopolysaccharide-stimulated macrophages and interleukin 1β activated epithelial cells. γ-tocopherol has properties that are not shared with α-tocopherol. γ-tocopherol is more effective as an anti-inflammatory and more efficient at quenching reactive nitrogen oxide species that are generated in chronic inflammation.

Tocotrienols benefit cardiovascular disease by inhibiting LDL oxidation and down-regulating 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG CoA) reductase, which is an essential enzyme of the mevalonate pathway (source). In addition, tocotrienols are capable of penetrating quickly through the skin and efficiently combatting UV or ozone-induced oxidative stress. Moreover, critical and novel anti-proliferative and neuroprotective effects of tocotrienols may be independent of their antioxidant activity (source).

Food Sources

Vitamin E can be found in wheat-germ oil, and vegetable oil, along with their seeds such as sunflower, avocado, sweet potato etc., and nuts such as hazelnuts, almonds, pecans, and peanuts. Substantial amounts of vitamin E may be lost due to processing, storage or cooking. A controlled study on healthy individuals confirmed that the plasma concentration of vitamin E and plasma antioxidant activity in response to oral supplementation of vitamin E are notably affected by food intake (source). It should be noted that vitamin E appears to be a poor indicator of plasma levels of vitamin E (source).

Furthermore, while increasing dietary vitamin E intake can increase plasma α-tocopherol levels, the amount of dietary modifications required to achieve potential cardioprotective levels of plasma α-tocopherol is unlikely in practice (source), and supplementation may be required. Due to the lipophilic nature of vitamin E, its absorption is increased with food intake and should be taken with meals. The requirement for vitamin E is closely related to the dietary intake of polyunsaturated fatty acids (PUFA). Vitamin E is metabolically consumed by a protective mechanism to prevent PUFA from being peroxidised. Thus some foods generally considered as sources of vitamin-E, as concluded from their gross vitamin E content, can cause a vitamin E deficiency if not sufficiently compensated by other vitamin E supplying food constituents (source). γ-tocopherol is the most prevalent form of vitamin E and is found in plant seeds, yet α-tocopherol is the form of vitamin E typically found in supplements. Interestingly, while the body preferentially accumulates α-tocopherol, γ-tocopherol has properties which are not shared by α-tocopherol.

Dose

The RDA for vitamin E is currently set in mg, though many supplement companies prefer to use International Units (IU’s). Depending on the source, the current RDI for vitamin E varies from 12-30 IU each day. In the year 2000, the Food and Nutrition Board of the Institute of Medicine published a new dietary reference intake of 15mg (22.4IU) (source). The increase in the RDA has been challenged and supported by others (source, source). The tolerable upper intake level has been reported to be 1,000mg (1,100IU) daily. Careful dietary selection may allow one to transcend the RDA of vitamin E. But it does not take into consideration the vitamin E depleting capacity of PUFA's (source), failing to reach the 100 IU per day minimal therapeutic recommendation (source), the 200IU which appears to be optimal for the immune status of the elderly, or the 400-800 IU that is necessary to reduce the risk of cardiovascular disease (source).

In addition to consuming 5-8 servings of fruit and vegetables in their daily diet, it has been suggested that people should take a supplement of 200 IU vitamin E (source). Vitamin E supplementation is not free of downsides. Synthetic vitamin E is a mixture of 8 isomers, of which only one has the RRR configuration that is found in natural vitamin E. The relative potency remains unproven, though in animals the potency of natural vs synthetic vitamin E is 1.36 (source). In comparison to the natural stereoisomer, RRR-alpha-tocopherol acetate, synthetic vitamin E is an equimolar mixture of eight stereoisomers (source).

The different tocol and tocotrienol derivatives alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-) have differing roles and diverse tissue affinities (source). An example is that studies are suggesting γ-tocopherol is required to adequately remove peroxynitrite-derived nitrating species despite α-tocopherols action as an antioxidant (source). Large doses of dietary α-tocopherol have been shown to displace γ-tocopherol in other tissues and plasma and may block this action, which may mean that the current wisdom of vitamin E supplementation with primarily α-tocopherol may require review and it may be beneficial to supplement with a full spectrum vitamin E supplement to gain the most benefit. Variations in the biologic activity of different forms of vitamin E presumably reflect the ease with which each molecule attaches to the cell surface. The biological activity of d-α-tocopherol is 1.49 IU/mg; in contrast, d-γ-tocopherol has a lower biologic activity of 0.15 IU/mg. Certainly, the vitamin E structure dictates its potency.

The standard for calculating the vitamin E content of food is α-Tocopherol content. One mg of natural vitamin E (RRR-α-tocopherol form), provides 1.49 IU of δ-α-tocopherol, while 1 mg of synthetic vitamin E, the all-rac-α-tocopherol form, provides 1.10 IU of dl-alpha-tocopherol. Synthetic vitamin E is inferior in comparison to natural vitamin E, with 1,000 mg of vitamin E providing 1500 IU and 1,000mg providing 1,100 IU respectively. The therapeutic dose ranges from 100 to 2000 IU per day.

Increased dietary consumption of unsaturated fat requires an increased intake of vitamin E. An increased vitamin E intake of 0.4 mg for each gram of linoleic acid and of 3-4 mg for each gram of eicosapentaenoic and docosahexaenoic acids (EPA and DHA) appear to be reasonable. As the concentration of polyunsaturated fatty acids in the diet increases, it is commonly acknowledged that the requirement for vitamin E increases. Nevertheless, a cross over trial has found that 400 mg α-tocopheryl acetate failed to change the small, but statistically significant, increase in oxidative stress reflected in plasma TBARS concentration after consuming fish oil with 2.5g EPA and 1.8g DHA daily (source). However, for those persons on a diet that is rich in polyunsaturated fatty acids, it may be untimely to halt vitamin E supplementation. A useful formula to consider is to supplement 0.4 mg of vitamin E for each gram of linoleic acid and 3-4 mg for each gram of EPA or DHA. Infants receiving a formula that is high in polyunsaturated fatty acids should be supplemented with at least 15-25 IU vitamin E each day or be given 7 IU of vitamin E for every 32 ounces of formula. Always store vitamin E supplements away from heat, damp areas and direct light.

Toxicity/Drug Interactions

The cost and safety profile of vitamin E favors empiric use in recommended doses (source). Within a therapeutic range of 200-1600 α-tocopherol equivalents, animal experiments have shown that vitamin E is not mutagenic, teratogenic or carcinogenic. Vitamin E is regarded as safe at levels up to 800 IU/day, and probably safe at doses of 1,600 IU/day. However, side effects may be expected to begin at doses of around 1,500 IU/day (source), even doses as high as 3,200 mg/day have been shown to be without any consistent risk (source). Nonetheless, some persons consuming vitamin E in doses greater than 400 IU daily over prolonged periods may experience blurred vision, diarrhea, dizziness, headache, nausea or stomach cramps, unusual tiredness, or weakness. Vitamin E decreases platelet adhesion and, at levels above 400 IU daily, may increase clotting times (source) Oral intake of high levels of vitamin E can exacerbate the blood coagulation defect of vitamin K deficiency caused by malabsorption or anticoagulant therapy (source). Provided the prothrombin time or international normalized ratio is tested on starting a new drug and repeated within 7 to 14 days of taking vitamin E, it is safe to use in combination with anticoagulants. Vitamin E, by antagonizing vitamin K and inhibiting prothrombin production, may increase risk of hemorrhagic strokes (source). Vitamin E has a number of nutrient-nutrient and nutrient-drug interactions. Vitamin E supplementation may impair the hematologic response to iron and should be avoided in iron deficiency anemia. Large doses of iron or copper may increase the requirement for vitamin E, while zinc deficiency reduces vitamin E plasma levels. The tocopherol radical can interact with vitamin C to restore tocopherol. On one hand, vitamin C has a sparing effect on vitamin E, and moderate doses of vitamin E have a sparing effect on vitamin A (source). On the other hand, large doses of vitamin E may deplete vitamin A and increase the requirement for vitamin K. Vitamin E may enhance the anti-inflammatory effect of aspirin and decrease the dose of anticoagulant, insulin, and digoxin required. Anti-convulsants, oral contraceptives, sucralfate, colestyramine, and/or liquid paraffin may reduce plasma levels of vitamin E (source).

Clinical Uses

It has been suggested that a daily intake range of 25-67 mg or 0.06-0.16 mmol vitamin E is optimal (source). A ratio of at least 1.3 to 1.5 vitamin C and E should be maintained to avoid oxidative stress. High intakes of α-tocopherol supplementation in humans have clearly shown to decrease lipid peroxidation, platelet aggregation, and that it functions as a potent anti-inflammatory agent according to epidemiologic studies (source). Vitamin E supplementation improves the immune system and offers some protection against cardiovascular disease and certain cancers (source). In all cases, doses are quoted in the units of the reference source.

Various studies suggest clinical uses of vitamin E in daily doses of the following:

  • 50-1500 mg to prevent cardiovascular disease.

  • 400 IU to reduce the risk of cataracts.

  • 20 mg for cancer prevention, increased to 50 mg daily to reduce the risk of prostate cancer in smokers. Data suggests that smoking increases the disappearance of vitamin E from the plasma. (source)

  • 800 IU in two doses of 400 IU to reverse leukoplakia or dysplasia.

  • 1600 IU for 8-12 weeks to alleviate symptoms of tardive dyskinesia. Antipsychotic (neuroleptic) medication, used to treat people with chronic mental illnesses, is associated with a suite of adverse effects, including movement disorders such as tardive dyskinesia. Small trials of uncertain quality indicate that vitamin E protects against deterioration of tardive dyskinesia, but there is no evidence that vitamin E improves symptoms (source)

  • 900 mg to reduce oxidative stress.

  • 900 mg to enhance insulin action in type 1 diabetes.

  • 60 mg in two doses of 30 mg daily to improve immune function. Immune function in the elderly improves on 800 IU/day (source).

Positive relationships between vitamin E intake and the prevention of atherosclerotic heart disease has been demonstrated in a literature search conducted between 1966 and 1999 (source). Positive outcomes such as a 77% reduction in nonfatal myocardial infarction, though there was no corresponding reduction in mortality. Two prospective cohort studies have suggested that persons taking 100-250 IU of vitamin E each day were less likely to have a major coronary event and patients with atherosclerosis on 400-800 IU of vitamin E daily were least likely to have a clinical cardiac event (source). Nevertheless, results from such studies are inconsistent. Although, basic science and animal studies have generally embraced the hypothesis that vitamin E may slow the progression of atherosclerosis. In addition, observational studies, primarily assessing patients without established coronary heart disease, have primarily supported the protective role of vitamin E. Yet initial primary and secondary prevention clinical trials have been disappointing and have failed to show a meaningful benefit from vitamin E (source). For example, a study using carotid ultrasound to evaluate atherosclerotic changes demonstrated benefit from angiotensin-converting enzyme (ACE) inhibitor, ramipril, but failed to show a difference with 400 IU of natural vitamin E. One reason for such failure may relate to the dose and isomers used. Vitamin E in doses under 50 IU/day is clinically worthless, doses over 100 IU/day may prevent or reduce the progression of coronary disease, while doses of above 1300 IU daily may be required to reduce the chance of restenosis (the recurrence of abnormal narrowing artery or valves after corrective surgery)(source).

The dose of vitamin E appears critical to its physiologic result. While doses of 400 IU α-tocopherol daily have a significant protective effect on LDL oxidation (source), at doses of 1200 IU/day, LDL oxidation is significantly greater (source). While normal plasma levels of vitamin E enhance lipoxygenation of arachidonic acid in vitro studies, yet higher concentrations have a suppressive effect (source). Daily doses of vitamin E in above 800 IU may adversely affect platelet function and 1200 IU per day may interfere with the function of vitamin K and granulocyte responses (source). Moreover, daily doses of vitamin E as high as 800 IU may enhance immunity, while doses in above 800 IU may suppress immunity. Although there currently may be insufficient evidence to recommend routine use of vitamin E for the prevention of coronary artery disease or stroke, some regard daily doses of 100-800 IU vitamin E useful for secondary prevention (source).

In addition to potentially benefiting persons with cardiovascular and cerebrovascular disease, vitamin E may assist those with peripheral vascular disease. Vitamin E is helpful for secondary prevention of intermittent claudication (pain caused by ischaemia in the muscles of the leg during exercise), providing the most benefit to those with the poorest collateral circulation and pedal blood flow (source). It could be necessary to maintain therapy for 12-18 months before benefits are observed. Doses vary for 400-1200 mg/day. However, there was insufficient evidence to determine whether vitamin E is an effective treatment for intermittent claudication in a review of clinical trials (source).

A placebo-controlled, clinical trial of 2000 IU (1342 α-tocopherol equivalents) of vitamin E per day in patients with moderately advanced Alzheimer’s disease suggested that vitamin E may slow functional deterioration (source). A double-blind, placebo-controlled, randomized, multi-center trial in patients with moderately severe Alzheimer’s disease demonstrated that α- tocopherol slows the progression of disease by 670 days (source). Vitamin E also delays the onset of memory deficits in animal models and prevents the oxidative damage induced by β-amyloid in cell culture. However, in a review of all unconfounded, double-blind, randomized trials in which treatment with vitamin E at any dose was compared with placebo (source) concluded that there was insufficient evidence for the efficacy of vitamin E in the treatment of people with Alzheimer’s disease.

Patients with type 1 diabetes should consider life-long supplementation of vitamin E. Increased vitamin E intake has been associated with enhanced glucose tolerance and insulin action (source). Pharmacologic doses of vitamin E and C increase insulin-stimulated cellular uptake of glucose. A double-blind study found that 250 IU (168 mg) of RRR-α-tocopherol taken three times/day reduced lipoprotein peroxidation in patients with type 1 diabetes (source). Type 2 diabetes has been associated with increased free radical production, lipid peroxidation, and reduced plasma vitamin E levels. The long-chain polyunsaturated fatty acid content of skeletal muscle phospholipid membranes are related to variations of insulin sensitivity.

Other likely applications for vitamin E involve incorporation as part of a more significant nutritional protocol to prevent cancer. Vitamin E inclusive protocols significantly lessen the incidence of prostate, bladder, and stomach cancers, and prevent recurrences of colonic adenomas (source). Through the stimulation of wild-type p53 tumour suppressor gene, down-regulation of mutant p53, heat shock protein activation, and an anti-angiogenic effect mediated by the blockage of transforming growth factor-alpha (TGF-α) are some of the mechanisms whereby vitamin E may impair carcinogenesis (source).

Hair Test Notes:

According to Dr Lawrence Wilson, “Vitamin E is also essential for adrenal gland activity, and for this reason, perhaps, tends to increase the oxidation or metabolic rate in all cases” (source)

Vitamin E and Selenium have a synergistic relationship (source, source) that effectively inhibit chemical carcinogens by accelerating their detoxification. Prolonged intake of selenium may cause a vitamin E deficiency and vice versa (source).

Clinical Caution

A daily intake of 4 mg vitamin E may result in a critically low plasma vitamin E level of 20-25 umol/L (30 umol/L is desirable). In reality, clinical deficiency is rare,  except in persons with fat malabsorption. A person may consume food-stuffs generally considered as sources of vitamin-E. However, these foods may cause a vitamin E deficiency (source).  Symptoms that suggest vitamin E deficiency include areflexia, psychologic syndromes, cognitive dysfunction, nystagmus, ataxia, muscle weakness, and sensory loss in the arms or legs (source). Other symptoms as a result of deficiency are lipid peroxidation, Alzheimer’s disease, infertility, menopausal symptoms, fatigue, restlessness, insomnia, anemia, creatinuria, cystic fibrosis of the pancreas, impaired circulation, general poor health, poor muscle development or muscle wasting, and asthma or other lung damage due to polluted air (source).

Practise Tips

  • To prevent deficiency, consider supplements of at least 60 mg (40.2 IU) for adult males and females, respectively.

  • Most studies suggest that the therapeutic effects of vitamin E are more likely when intake exceeds 100 IU per day, possibility 200-400 IU per day.  

  • Different antioxidants appear to act synergistically, so supplementation with vitamin E might be more effective if combined with other micronutrients.

  • Combined daily supplementation of vitamin E (200 mg) with vitamin C (1000 mg) function synergistically and enhances immunity more than either vitamin alone.

  • γ-tocopherol form of vitamin E is indicated to reduce chronic inflammation, including atherosclerosis (source).

  • Supplementation with α-tocopherol decreases tissue levels of γ-tocopherol while supplementation with γ-tocopherol increases tissue levels of both α- and γ-tocopherol.

  • At levels of 300-1000 IU, vitamin E appears free of side effects.

  • Supplementing selenium may minimise the effect of deficiency of vitamin E.

  • Muscle cramping may be eased by vitamin E (500 IU daily).

  • Dysmenorrhea may respond to 250 IU alpha-tocopherol twice daily starting ten days premenstrually and continuing for fourteen days.

  • Vitamin E and selenium protect against mercury and silver toxicity (source, source).

  • Vitamin E has anti-estrogenic effects (source,source).

Additional Reading

https://academic.oup.com/ajcn/article-abstract/8/4/451/4829432?redirectedFrom=fulltext

https://www.nrv.gov.au/nutrients/vitamin-e

http://raypeat.com/articles/articles/vitamin-e.shtml

https://www.drlwilson.com/ARTICLES/VITAMINS.htm