Sunday, April 27, 2014

The Vitamins E & Glucose Control | Part X of the "There is More To Glucose Control Than Low Carb" | Plus: Alpha-, Gamma-, Delta-Vitamins E, Where Can You Find Them?

All nuts are good tocopherol (T) sources, but α- T is predominantly found in peanuts, almonds and sunflower seeds, while γ-T is the major vitamin E in walnuts, pecans and pistachios.
Over the past week I've been questioning the potency of various supplement superstars with respect to their ability to improve your, my or any one else's glucose metabolism. We've dealt with protein, peptides, fats, vitamin D, calcium, a whole host of B-vitamins and even the underrated vitamin A (go back and review all of them).

Today I am going to take a look at a "fallen star", vitamin E, once thought of as a panacea and universal protector of your cells, it has, at the latest with publication of the disappointing, if not shocking results of the SELECT trial in 2013 and the mass-media reverberations about increased prostate cancer risk, become the centerpiece (literally) of every anti-vitamin supplement rant.
You can learn more about this topic at the SuppVersity

Proteins, Peptides & Blood Glucose

SFA, MUFA, PUFA & Blood Glucose

Vitamin D & Diabetes

Glucose Manager Calcium?

Flush & No-Flush Niacin & Diabesity

Vitamin C & Glucose Control
Table 1: Tocopherol / -trienol compo-sition of select oils (Juang. 2014); mind the association of PUFA + γ- and MUFA + α-tocopherol.
You will probably remember that I have criticized the design and interpretation of the results of the often- and in my eyes over-cited SELECT trial on several occasions. And even if there was a +17% increase in cancer risk in young men who are stupid enough to take 400 IU of all rac-α-tocopheryl acetate, everyday (Klein. 2011), this does not necessarily exclude that the same effects occur if the vitamin E comes from a natural source and contains the whole vitamin E alphabet from alpha- over gamma to delta-tocopherol.

Not in spite of, but rather because of the existing evidence that vitamin E could cause prostate cancer and, when it's consumed with vitamin C, inhibit the beneficial adaptation processes that are triggered by the "eu-stressor" (=good stress) exercise, it is yet even more important that we take a closer look at the actual negative effects vitamin E supplements exert on your ability to control your blood sugar levels.

Vitamin E  ➫ insulin resistance ➫ cancer?

I mean, think about it: What is the best growth environment for cancer? Right, sugar coated cells - a study by Stattin et al. (2007) has after all been able to show that to an the risk of developing any form of cancer increases almost linearly from the bottom to the top quartiles of fasting and postprandial glucose levels.
Figure 1: Risk increase for various cancer if fasted [F] and post-glucose load [P] blood glucose levels are in the fourth vs. first quartile; the hazard ratios were calculated based on data from the 33,293 femal and 31,304 male subjects of the Västerbotten Intervention Project of northern Sweden (Stattin. 2007)
If we assume that vitamin E does inhibit the anti-diabetic adaptations to exercise (in conjunction with vitamin C, it does just that; cf. Ristow. 2009), it would increase the risk of having extreme blood sugar excursions, of which the data in Figure 1 reveals that they, in turn, could be the reason vitamin E was found to be associated with an increased cancer risk.
Prostate cancer and high glucose levels? Unlike other forms of cancer, prostate cancer does not appear to flourish in high glucose environments. At least that's what the epidemiological evidence suggests. Evidence which may be flawed by the existence of a genetic variant with opposite effects on risk of type 2 diabetes and prostate cancer (Gudmundsson. 2007), which could partly explain the null association between glucose and prostate cancer in our study as well as the consistently reported reduced risk of prostate cancer in men with type 2 diabetes (Kasper. 2006).
The question we have to answer in today's installment of the "There is More to Glucose Control Than Low Carb", would thus be: Does vitamin E a protective, a detrimental, or no influence on the development of insulin and type II diabetes ... and the answer is: As usually, complicated.

First things first - What actually is vitamin E?

I have already hinted at the fact that "vitamin E" is a generic term that is usually falsely applied to alpha-tocopherol, only. When we are talking about vitamin E, we do yet have to look at the whole spectrum of vitamins E, which include the three tocopherols, as well as their rare tocotrienol buddies.

Tocopherols - α-, γ, and δ- and relates substancesTocotrienols - α-, γ, and δ- and related substances
They are a class of chemical compounds many of which have vitamin E activity. This series of organic compounds consists of various methylated phenols. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rats, it was given the name "tocopherol" from the Greek words "τόκος" [birth], and "φέρειν", [to bear or carry] meaning in sum "to carry a pregnancy," with the ending "-ol" signifying its status as a chemical alcohol.
α-Tocopherol is the main source found in supplements and in the European diet, where the main dietary sources are olive and sunflower oils, while γ-tocopherol is the most common form in the American diet due to a higher intake of soybean and corn oil.
There is no RDA or other recommendation for the intake of the three most common tocopherols, i.e. α-, γ, and δ- tocopherol. The currently recommended intake for "vitamin E" is thus based on the concept of alpha-tocopherol equivalents. A very sketchy idea that's probably flawed due to significant differences in the metabolism and uptake of the various tocopherols between rodents and humans.
In view of the fact that dietary vitamin E provides - assuming you don't follow the standard American diet - a balanced mix of tocopherols, you don't really have to care about the accuracy of the conversion factors.
Tocotrienols are members of the vitamin E family. An essential nutrient for the body. The slight difference between tocotrienols and tocopherols lies in the unsaturated side chain having three double bonds in its farnesyl isoprenoid tail.
Tocotrienols are natural compounds found in select vegetable oils, including rice bran oil and palm oil, wheat germ, barley, saw palmetto, anatto, and certain other types of seeds, nuts, grains, and the oils derived from them. This variant of vitamin E typically only occurs at very low levels in nature.
At the moment we still know too little about this form of vitamin E to be able to tell how much of them you actually need. It is in fact not even sure that they are necessary at all.
Contemporary evidence does yet appear to suggest important functional differences between tocopherols- and -trienols that have the latter appear as the more potent cousins of the good old tocopherols. Furthermore, emerging evidence suggest that some long-chain vitamin E metabolites have even stronger anti-inflammatory effects than their vitamin precursors.
Unless you plan to live on artificial foods, alone, the rare tocotrienols will yet never fully replace the omnipresent tocopherols.
Table 2:Brief overview of some of the basic fact about the two main forms of vitamin E (partly based on the Wikipdia entries and on information from a soon-to-be-published review by Jiang)
This is unfortunately, where things get complicated. For one, 99% of the studies have been conducted with alpha-tocopherol, only. For two, the vast majority of the few studies that investigate potential effects of other "vitamins E" on glucose control use either another form of tocopherol, or tocotrienols. A study that would investigate the effects of the whole spectrum of vitamins E, let alone their interactions, on the other hand, has still to be conducted.

☇ Let's start with epidemiological evidence, today

That being said, out best and most realistic starting point is not the classic randomized controlled trial, but "epidemiological guesswork". As long as we are talking about food-borne vitamin E, we are always talking about a natural mix. A mix, which was (unfortunately) often measured in alpha-tocopherol units, but would, in the absence of supple of which studies show that the following associations (remember: epidemiology cannot prove cause-effect relationships)
  • Low vitamin E intakes (<10mg/day, i.e. 15IU) have been associated with and correspondingly low serum levels have been associated with 3.9x increased diabetes risk back in 1995, when vitamin E was still everybody's darling (Salonen. 1995). In view of the relatively low threshold level, this is yet rather a study that supports the notion that vitamin E is, just as the word "vitamin" implies, so vital for your health that you better make sure you get enough of it from your diet (the RDA is 15mg/day).
  • Table 3: The number of studies that distinguishes the different forms of vitamin E is low. A 2004 study by Montonen et al. does yet appear to confirm what I wrote before - they are all relevant and the the 34% reduced diabetes risk with a high dietary alpha-tocopherol intake is by no means meaningless.
    Significantly and borderline significantly reduced type II diabetes risks with all forms of tocopherols and tocotrienols in a cohort consisting of  2,285 men and 2,019 women 40–69 years of age who were free of diabetes at baseline when they were recruited for a 23-year follow-up in 1967–1972 (Montonen. 2004).

    What is particularly interesting is that the data in Table 3 clearly indicates that the good old, often ridiculed alpha-tocopherol does still have the most potent anti- diabetes effect of all 6 forms of vitamin E.

    Moreover, with beta-tocotrienol, the 2nd place is however occupied by a form of vitamin E you will find in very high amounts (30µg/g; cf. Nielsen. 2008) in whole wheat grain - is this the reason whole grains are associated with lower type II diabetes risk in epidemiological studies (Cho. 2013)?
  • High intakes (>20mg/day, i.e. only 30IU!) of vitamin E are associated with a ~20% reduced risk of developing type II diabetes in the participants of the Insulin Resistance Atherosclerosis Study (IRAS) that involved 895 nondiabetic adults at baseline (including 303 with impaired glucose tolerance [IGT]), 148 of whom developed type 2 diabetes according to World Health Organization (WHO) criteria during the 5-year follow-up (Mayer-Davis. 2002)
Epidemiology, dietary vitamin E and high dose supplementation: Most epidemiological studies still measure the alpha-tocopherol intake and serum levels. As long as there are no supplements involved, the results will yet still be representative of dietary vitamins E intake. It's after all more or less impossible to get only one form of vitamin E from whole foods.
That being said, "officially" the consumption of alpha-tocopherol-only supplements is save - at least in amounts of 60, 200, or 800 IU/day (55, 182, or 727 mg) all-rac-a-tocopherol/d will not produce noticeable side effects, changes in body weight, plasma total proteins, albumin, glucose, plasma lipids or the lipoprotein profile, the whole set of measures of organ health, as well as the levels of antioxidant vitamins and minerals (including the other forms of vitamin E; Uchida. 2013), glutathione peroxidase, superoxide dismutase, or total homocysteine of healthy elderly individuals (Meydani. 1998). Bendich & Machlin even state that vitamin E was safe up to doses of 3,200IU/day. Personally I do yet strongly advice against using more than 1,200IU of E per day (Bendich. 1988) - irrespective of whether it's alpha tocopherol or a tocopherol and -trienol blend.
  • Liver Enzymes the #1 Marker of Insulin Resistance | learn more
    Patients with non-alcoholic fatty liver disease consume on average only half the amount of vitamin E, their healthy peers do (Musso. 2003). As a SuppVersity reader you know about the intricate relation between NAFLD and diabetes, and are thus aware that this is another "pro" argument with respect to the consumption of high vitamin E foods. If this is your first visit to the SuppVersity check out my previous article "Liver Enzymes the #1 Marker of Insulin Resistance!? Plus: What Does the Correlation Bettwen HbA1C & ALT, AST and GPT Tell Us About Diabesity?" to learn more about the relationship between obesity, diabetes and non-alcoholic fatty liver disease.
On the other hand of the "foods vs. supplement divide" things are less black or white, though. While the previously cited epidemiological evidence clearly suggests that food-borne vitamin E will protect you against diabesity. On the "supplement side of things", we have both extremely promising positive experimental evidence:
  • 42% increased glucose disposal in elderly study participants in response to mediated stimulation after 4 months on a 900 mg d-alpha-tocopherol, i.e. 1350IU (!) of supplemental vitamin E per day. The fact that Paolisso et al. also observed that the "net changes in plasma vitamin E concentrations correlated with net changes in insulin-stimulated whole-body glucose disposal (r = 0.60 P < 0.003)" makes their results even more amazing (Poalisso. 1994)
  • Low vitamin E intakes early in pregnancy have been found to set women up to insulin resistance and hyperglycemia later in pregnancy by Ley et al. who write in their recent paper in the European Journal of Clinical Nutrition that (Ley. 2013) even after adjustment for serum adiponectin among women consuming daily, higher dietary vitamin E intakes were associated with lower fasting glucose, lower HOMA insulin resistance (long term measure of blood glucose), and higher Matsuda insulin sensitivity index (standard measure to quantify insulin sensitivity) among women who consumed a faily multivitamin supplement with "adequate", albeit probably synthetic vitamin E (dl-alpha-tocopherol).
The specificity principle: I am not sure if you remember the "Three Simple Rules of Reasonable Supplementation" (re-read them), but if you do, you will remember that specificity is one of the most important principles to follow, if you want to make the most of your supplement regimen. In the case of alpha-tocopherol this may mean that benefits will be seen in people with high baseline inflammation, while people without chronic inflammation, will see no, or even experience negative effects from (high) dose vitamin E supplements.
  • Modest vitamin E supplementation  (100 IU/day) can significantly lower blood glycated hemoglobin and TG levels and does not have any effect on red cell indices in Type I diabetic patients (Jain. 1996). In view of the inflammatory underpinnings of type I diabetes, this study is yet not exactly representative of the benefits a healthy individual may derive from the same amount of vitamin E... although, I have to admit that a 100IU supplement looks much more rational to me than one with 400-1,200IU - specifically if it's pure alpha-tocopherol.
  • High dose (800-1200 IU/day) vitamin E supplementation improves fasting blood glucose and HbA1c levels in obese subjects - eighty overweight individuals (BMI >27 kg/m²), to be precise, who  were randomly allocated to receive either 800 IU vitamin E per day or a matching placebo for 3 months. The dose of vitamin E was increased to 1,200 IU per day for a further 3 months (Manning. 2006).
On the other hand, we have experimental evidence that refutes the previously reported beneficial effects of supplemental vitamin E on blood glucose management. Examples? Here you go:
  • And what about exercise: Aside from the previously mentioned negative effects on the adaptation triggering exercise induced eustress, there are no good reasons to avoid vitamin E supplements for athletes. In fact, my previous analyses of corresponding studies here at the SuppVersity would suggest that people with a high baseline inflammation that overrides the exercise-induced locally confined increase in inflammation, may have good reason to take up to 400 IU/day of mixed tocopherols (opt. -trienols) - specifically if their vitamin E intake from foods is low, like on a diet, for example.
    600 IU/day of vitamin E taken every other day provided no significant protection against type 2 diabetes in initially healthy women in the Women’s Health Study randomized trial (Liu. 2006). A study that appears to confirm that supplementing additional antioxidants is, just like keeping your omega-3/omega-6 ratio up (learn more), useless, unless it's part of an overall healthy life-style - and in that case, there is still the nasty question: Will it negate the beneficial effects of exercise or not?
  • In general, vitamin E supplementation does not decrease all-cause mortality or cardiovascular disease risk in type II diabetes. This is at least what a 2003 meta-analysis of studies with 81,788 concluded. As Vivekananthan et al. point out, "the lack of a salutary effect was seen consistently for various doses of vitamins in diverse populations" (Vivekananthan. 2003)
Of particular interest for us is the conclusion Vivekananthan et al. draw based on the results of their meta-analysis: If their results "do not support the routine use of vitamin E" this does after all mean that we don't have to argue about whether or not antioxidants negate the beneficial effects of exercise or whether "high-dosage vitamin E supplementation may increase all-cause mortality" as Miller et al. (2005) suggest in a 2005 meta-analysis in the Annals of Internal Medicine - Why? Well, why would we care about negative side effects, if it's not worth using them, anyways!?
α-tocopherol: Veggies (spinach, broccoli, tomato paste, everything that's orange); eggs; almonds, peanuts, sunflower seeds; olive & almond oil.
γ-tocopherol: tomotoes, tuna; eggs; walnuts, pecans, pistachios and sesame seeds, pine nuts; dark chocolate or baking chocolate; seeds & grains, flax, peas, lentils; corn, soybean & canola oil, margarines, all sorts of shortenings and fried foods that are prepared with high γ-tocopherol oils
δ-tocopherol: peppers, onions, tomato seeds; raspberries, black- berries; tuna, mol- lusks, eggs; edamame; orega- no; rice germ oil, soy- bean oil, all sorts of shor- tenings and fried foods that are prepared with high δ-tocopherol oils
Don't supplement, eat your vitamins E: Not using vitamin E supplements (for glucose management) does yet also imply that you have to get your vitamins E from dietary sources. In view of an RDA of only 15mg and evidence that 100mg of vitamin E is already plenty, this does not appear to be difficult, but if you look at the total amount of vitamin E in the average American diet, you will be surprised that (a) gamma- and not α-tocopherol is the major form of vitamin E in the vegetable oil laden US diets (~60-70 % γ- vs. 20-25% α-tocopherol; cf. McLaughlin. 1979) and that (b) more than 80% of the Americans who don't supplement and still 45% of those who take supplements are effectively vitamin E deficient (McBurney. 2014).

There is little doubt that McBurney's observations are partly related to the increase vitamin E requirements of a lifestyle that is characterized by junk-food diet, sedentarism and chronic inflammation. They are yet also a result of a lack of foods that are naturally high in vitamin E, and supply you with both, the full spectrum of tocopherols and -trienols and the necessary co-factors to make the most of your dietary vitamins E intake - in short, it's a lack of the foods in the list on the right. Foods of which I assume that I will find the healthy ones (in italics) on your plate regularly, right?

What? Oh, yes. Well, the tocotrienols are in fact a problem. With the exception of red palm oil (50-75mg/100g) you will find only trace amounts (all values in mg/100g) of them in various fats/oils like rice wheat germ oil (18.9), coconut oil (2.1), and cacao butter (0.2) and grains like barley (91) and oats (21).
Reference: 
  • Bendich, A., and L. J. Machlin. "Safety of oral intake of vitamin E." The American journal of clinical nutrition 48.3 (1988): 612-619.
  • Cho, Susan S., et al. "Consumption of cereal fiber, mixtures of whole grains and bran, and whole grains and risk reduction in type 2 diabetes, obesity, and cardiovascular disease." The American journal of clinical nutrition 98.2 (2013): 594-619.
  • Gudmundsson, Julius, et al. "Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes." Nature genetics 39.8 (2007): 977-983. 
  • Jain, Sushil K., et al. "Effect of modest vitamin E supplementation on blood glycated hemoglobin and triglyceride levels and red cell indices in type I diabetic patients." Journal of the American College of Nutrition 15.5 (1996): 458-461. 
  • Jiang, Qing, et al. "γ-Tocopherol, the major form of vitamin E in the US diet, deserves more attention." The American journal of clinical nutrition 74.6 (2001): 714-722.
  • Jiang, Qing. "Natural forms of vitamin E: Metabolism, antioxidant and anti-inflammatory activities and the role in disease prevention and therapy." Free Radical Biology and Medicine (2014).
  • Kasper, Jocelyn S., and Edward Giovannucci. "A meta-analysis of diabetes mellitus and the risk of prostate cancer." Cancer Epidemiology Biomarkers & Prevention 15.11 (2006): 2056-2062.
  • Klein, Eric A., et al. "Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT)." Jama 306.14 (2011): 1549-1556.
  • Ley, S. H., et al. "Lower dietary vitamin E intake during the second trimester is associated with insulin resistance and hyperglycemia later in pregnancy." European journal of clinical nutrition (2013).
  • Liu, Simin, et al. "Vitamin E and risk of type 2 diabetes in the women’s health study randomized controlled trial." Diabetes 55.10 (2006): 2856-2862. 
  • McBurney, Michael, et al. "Vitamin E status of the US adult population by use of dietary supplements (1041.7)." The FASEB Journal 28.1 Supplement (2014): 1041-7.
  • Manning, Patrick J., et al. "Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects." Diabetes Care 27.9 (2004): 2166-2171.
  • Mayer-Davis, Elizabeth J., et al. "Plasma and Dietary Vitamin E in Relation to Incidence of Type 2 Diabetes The Insulin Resistance and Atherosclerosis Study (IRAS)." Diabetes Care 25.12 (2002): 2172-2177. 
  • McLaughlin, P. J., and John L. Weihrauch. "Vitamin E content of foods." Journal of the American Dietetic Association 75.6 (1979): 647-665.
  • Meydani, Simin Nikbin, et al. "Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults." The American journal of clinical nutrition 68.2 (1998): 311-318.
  • Miller, Edgar R., et al. "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality." Annals of internal medicine 142.1 (2005): 37-46.
  • Montonen, Jukka, et al. "Dietary antioxidant intake and risk of type 2 diabetes." Diabetes Care 27.2 (2004): 362-366. 
  • Nielsen, Merete Møller, and Åse Hansen. "Rapid high-performance liquid chromatography determination of tocopherols and tocotrienols in cereals." Cereal chemistry 85.2 (2008): 248-251.
  • Paolisso, Giuseppe, et al. "Pharmacological doses of vitamin E and insulin action in elderly subjects." The American journal of clinical nutrition 59.6 (1994): 1291-1296.
  • Salonen, Jukka T., et al. "Increased risk of non-insulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men." Bmj 311.7013 (1995): 1124-1127.
  • Stattin, Pär, et al. "Prospective study of hyperglycemia and cancer risk." Diabetes care 30.3 (2007): 561-567.
  • Uchida, Tomono, et al. "α-Tocopherol does not Accelerate Depletion of γ-Tocopherol and Tocotrienol or Excretion of their Metabolites in Rats." Lipids 48.7 (2013): 687-695.
  • Vivekananthan, Deepak P., et al. "Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials." The Lancet 361.9374 (2003): 2017-2023.