I would not expect "red palm olein wonders", but more RPO and less corn oil in the American diet may at least buffer the liver disease burden in the US (the figure is based on data provided by the American Liver Foundation)
On Turesday, November 19, 2013, you've learned from a study by Subermaniam et al. about the "anti-rust" effects of coconut oil (if you missed that, you can catch up here), today, we are going back to Malaysia and the Universiti Kebangsaan Malaysia and the results of another team of researchers to learn about the effects the various oils have on the "oiling of the liver" (Dauqan. 2013).
I guess most of you will remember my previous comments about the critical role of the liver (and its health or disease) in the development of the metabolic syndrome (read it up). It is thus by no means irrelevant, whether the chronic ingestion of a certain type of oil will result in MDA levels of 92µmol/g or 27.3µmol/g.
Boring!? No, rather surprising!
If you think this sounds boring and are by no means surprised that the malondialdehyde levels of the liver samples the researchers harvested after 4 weeks were 27.3µmol/g, 92µmol/g, 54µmol/g, 47.4µmol/g and 72.6µmol/g for the control diet with mixed fats, red palm oloein (RPO), regular palm oil (PO), corn oil (CO) and the previously celebrated coconut oil (COC), respectively, I would suggest you have a closer look at the the "magic" that happened over the following 4 weeks of on 15% RPO, PO, CO and COC diets.
Figure 1: MDA levels (µmol/g) of liver tissue as a marker of lipid oxidation after four and eight weeks on control diet or control diet with 15% of red palm olein, palm oil, corn oil or coconout oil (Dauqan. 2013)
Well, you see, the way the effects of red palm olein came full circle after another months on the 15% RPO diet is hardly "boring", is it? The MDA levels, a relatively reliable indicator of local lipid oxidation, of the rodents on the 15% red palm olein diet is now, 4 weeks after peaking at 92µmol/g down to 25.2µmol/g, indicating that the level of lipid peroxidation in the livers of the RPO group is now significantly lower than that of any other group (43.4µmol/g, 50.1µmol/g and 48.3µmol/g for control, palm oil, corn oil and coconut oil).
Short term detriments, long term benefits!
I know it sounds more than awkward, but eventually every SuppVersity student should be aware of the fact that the extrapolation of long-term effects from short-term data is a 'risky' business. Unfortunately, even 'experts' often disregard this fundamental rule, when they formulate their recommendations on nutrition, supplementation and exercise.
Table 1: Carotenoid and vitamin E composition (in %) of crude palm oil and red palm olein; the data is from a different study by Bonni & Choo who tested commercially available products (Bonni. 2000)
The statement, "Prefer coconut oil and avoid red palm olein!", for example would have been a reasonable dietary if we did not know about the turn-around in the second part of the study, when the beneficial effects of the saturated fat content of the coconut oil begin to fade and the absence of natural anti-oxidants in refined coconut oil begins to show its ugly face. At this point, the moderate amount of unsaturated fats in red palm olein (13% omega-6, 0% omega-3; see Bonnie. 2000), of which I am honestly not sure if it is the actual reason of the initial increase in lipid peroxidation (remember: corn oil has more PUFAs!), or whatever other underlying cause of the initial rise in inflammation is overriden by the accumulating amounts of vitamins E and carotenoids from the red palm olein, which rendered the liver of the oxidation-proof, or "rustless" if you will - similarly rustless as the hearts of the rogents in the previously cited study by Subermaniam et al. (learn more).
200g of palm fruits have the same amount of tocotrienols as 4kg of oats. Learn more "tocotrienol" and red palm oil facts in "Tocotrienols: What They Are, What They Do & How They Work + Why the RDA of Palm Olein is NOT 1xCup Per Day " | more
Bottom line: I would like to formulate two take home messages for today's SuppVersity article. Firstly, a theoretical one, which shall remind you of the fact that you can do more harm than good, if you (accidentally) terminate a study in a transitional state and formulate long-term dietary recommendations based on short-term observations, because the study at hand clearly indicates that some effects - in this case the antioxidant effects of the tocopherols, -trienols and carotenoids - take their time to become measurable. And seconfly a very practical one, which is eventually only a reminder of the existence of red palm oil (see article referenced on the right) - an excellent source of dietary antioxidants and probably your only chance to get your tocotrienols and high(er) amounts of some of the rarer carotenoids from regular foods.
References:
Bonnie, T. Y. P., & Choo, Y. M. (2000). Valuable minor constituents of commercial red palm olein: carotenoids, vitamin E, ubiquinones and sterols. Journal of Oil Palm Research, 12(1), 14-24.
Dauqan, E., Abdullah, A., & Sani, H. A. (2013). LIPID PEROXIDATION IN RAT LIVER USING DIFFERENT VEGETABLE OILS. Malaysian Journal of Analytical Sciences, 17(1), 300-309.
Valls, V., Goicoechea, M., Muniz, P., Saez, G. T., & Cabo, J. R. (2003). Effect of corn oil and vitamin E on the oxidative status of adipose tissues and liver in rat. Food Chemistry, 81(2), 281-286.
Fried butter on a stick - I bet there are more peroxides in the crust than in the butter beneath it.
Yesterday we have taken a look at the saturated fat content of the diet and its effects on body composition, insulin resistance and inflammatory markers (see "Study Shows Doubling Saturated Fats Would Yield More Benefits Than Halving Them"). Today, we are going to look at the effects of a way not just Americans, but more or less half of the globe likes to process their foods on the oils and subsequent health of someone who would consume these oils on a regular basis. By now, you will probably already know into which direction this post is heading. Right, we are talking about frying, about lipid oxidation and about the health effects of oxidized soy bean and palm oil the #1 "choices" in processed foods.
Oxidized frying oils and their effects on our health
The paper by Jaarin and Kamisah, two researchers from the Department of Pharmacology at the Universiti Kebangsaan Malaysi in Malaysia is certainly not the only, maybe not even the latest study dealing with this issue, what I like about it though, is the fact that they don't use some sort of standardized oxidized oil, but actually went through the following unquestionably not unrealistic procedure to obtain their frying oils:
"A kilogram of sweet potato slices were fried in a stainless steel wok containing two and half litres of palm oil or soy oil for 10 minutes at 180°C. Upon completion of the frying process, once heated oil was obtained. The process was repeated four times to obtain five times heated oil with a cooling interval of at least five hours. The food quantity was proportionately adjusted with the amount of vegetable oil left. No fresh oil was added between the frying processes to make up for the loss due to uptake by the frying materials." (Jaarin. 2012)
After the oils had been heated, a small quantity was extracted and the peroxide value, fatty acid composition and vitamin E content measurements (another strength of the study, most other studies discard the fatty acid composition and vitamin E content).
Figure 1: Peroxide levels (data expressed relative to fresh palm oil) of palm and soy oil after frying at 180°C for 10minutes once or five times (based on Jaarin. 2012)
If you take a look at the peroxide values in figure 1 you see that the peroxide values in both the palm and the soy oil increased significantly after only one heating process (10min at 180°) already and -- at least in the case of soy oil -- exceeded the established maximally allowed value (red line). The palm oil, on the other hand is slightly below the margin. Now that obviously does not mean that the palm oil was still 100% healthy, while the soy oil was toxic waste - it's rather an artifice due to the arbitrarily set 10meq/kg limit for lipid peroxides in oils that are meant for human consumption (the Japanese must by the way be 'peroxide proof' because their laws allow concentrations up to 30meq/kg!).
Figure 2: Relative fatty acid composition of the fresh, once or five times heated oils (based on Jaarin. 2012)
A mechanistic explanation for the fact that the soy oil presents a higher total peroxide level than the palm oil can easily be derived from the data in figure 2. As you can see,...
"[...t]he fresh soy oil contained about five times more polyunsaturated fatty acid compared to the palm oil. It seemed that five times heating had reduced about 10% of the polyunsaturated fatty acid content in the soy oil. The content of monounsaturated fatty acid in the fresh palm oil was higher than that of the fresh soy oil. Palm oil had a quite balanced ratio of saturated and unsaturated fatty acids, whereas more than 70% of soy oil fatty acid was unsaturated (polyunsaturated and monounsaturated). This unique fatty acid composition of palm oil renders its stability against oxidative insult." (Jaarin. 2012)
Now, both the oxidation process during heating as well as the in vivo oxidative effects of the consumption of those oils does not depend on their fatty acid makeup and oxidation status, only, but is also affected by the amount of antioxidants, in particular vitamin E, the respective oil brings to the table.
Figure 3: Relative amount of tocopherols and tocotrienols that remained in the oils after frying (left) and effects of the consumption of a diet containing 15% of the oils + 85% standard rodent chow for 4 months on male and ovariectomized rats that received additional +2% cholesterol in their diets on thiobarbituric acid reactive substances (TBARS), astandard marker of lipid oxidation (right;(based on Jaarin. 2012)
In that, the vitamin E content is not only important to protect you from the effects of the peroxides that are already in the oil, they are at least as important to protect the polyunsaturated fatty acids you consume from being oxidized in your body.
Against that background, is should be obvious that the profound reductions in both tocopherols and tocotrienols will augment the negative effects, so that it is actually not that surprising that the amount of thiobarbituric acid reactive substances (TBARS = standard marker of lipid oxidation) in the blood of the rodents which consumed the diets with 15% of the five times heated palm and soy oil more than doubled.
Figure 4: While olive oil is more stable than corn and soy, it's not 'oxidation proof either' what's also intriguing is the amount of oxidation that is induced just by exposing the oil to air or air and light for 30 days! (Naz. 2012)
Putting things into perspective: While I would hope that no one of you will use the same oil for frying twice or thrice, let alone five times, I am not so sure about the foods you would be served at the university canteen, let alone the fast food store around the corner. Against that background, it is however still at least unsettling to see that even when you are frying potatoes or meats in a pan at home, the T-BAR levels rise significantly.
I assume that no one of you will use soy oil and only few will be cooking with palm oil, but I know that many people still use olive oil in a hot pan for several minutes. And while I do not have data from the same study, the data in figure 5 wouldsuggest that olive oil is probably as susceptible to heat as palm oil (if you go by the relations of palm:soy in the study at hand and olive:soy in the study by Naz et al.). If we go by this rule of thumb estimate, baking your potatoes in olive oil may not kill you, but clearly isn't the best way either.
Coconut oil!? No, unfortunately even the wonder oil does not come to a rescue. At least if we go by the data Matthäus obtained in 2007, it produces about as much peroxides as palm oil during the frying process (Matthäus. 2007). That's better than soy, and way below the critical margin, but still not without consequences on the overall oxidative burden you are exposing yourself to, when you consume significant amounts of fried foods on an everyday basis - and since I know that you do only have your occasional piece of fried grass fed butter on a stick, you won't have to be afraid anyway ;-)
Suggested reads:
Pimp my virgin olive oil - Discusses among other things how the polyphenols stabilize the vitamin E and render EVOO more heat stable than regular olive oil.
Vitamin(s)! E - A brief reminder that there is more than alpha-tocopherol + some evidence that delta tocopherol is king, when it comes to protect dietary oils
References:
Matthäus, B, Use of palm oil for frying in comparison with other high-stability oils. Eur. J. Lipid Sci. Technol. 2007;109: 400–409.
Jaarin K, Kamisah Y. Repeatedly Heated Vegetable Oils and Lipid Peroxidation. Intech. 2012.
Naz S, Siddiqi R, Sheikh H, Sayeed SA. Deterioration of olive, corn and soybean oils due to air, light, heat and deep-frying Food Research International, Volume 38, Issue 2, March 2005, Pages 127–134.
Which of the dirty dozen of supplements and foodstuffs in today's SuppVersity review can really help you to make sure, you're not the one out of those nine men who develops prostate cancer?
Supplements that are supposed to protect you from developing prostate cancer and/or agents that may help patients with existing prostate issues are - obviously - in high demand. And as W. Merkle points out in a recent article in the German science journal Urologe using them - even if they may not be as effective as some patients may believe - makes sense: from a psychological perspective, alone (Merkle. 2014).
Taking a pill with selenium, for example, has been shown to alleviate some of the side effects of chemotherapy. General protective effects against prostate cancer, on the other hand, have not been established. In fact, the most recent studies rather suggest that "supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status" (Kristal. 2014).
Supplements are nice, but without exercise you are missing 50% of the anti-cancer equation!
Tri- or Multi-Set Training for Body Recomp.?
Alternating Squat & Blood Pressure - Productive?
Pre-Exhaustion Exhausts Your Growth Potential
Full ROM ➯ Full Gains - Form Counts!
Battle the Rope to Get Ripped & Strong
Hula Hooping to Spot Reduce in the Midsection
Luckily, there are other supplements with more promising data. Supplements that will actually complement, a healthy diet and active lifestyle, the two pillars of all (not just prostate) cancer protection. Supplements like...
Curcumin - As a SuppVersity reader you've probably already expected to see the curcumin on the list. Its potent anti-inflammatory effects and more specifically its ability to target multiple inflammatory pathways, which include NF-KappaB, COX2, STAT3 and high levels of CRP, Prostaglandins and TNF-alpha make it a particularly valuable anti-tumor agent of which Guo et al. observed in a recent study that it will induce cell cycle arrest and apoptosis of prostate cancer cells by regulation the expression of IkappaBalpha, c-Jun and androgen receptor (Guo. 2013)
Genistein - Just like curcumin, genistein acts on NF-KappaB (Adjakly. 2013). In addition it will upregulate a protein called miR-574- 3p that will have cancer cells "kill themselves" (go into apopotosis; Chiyomaru. 2013). In addition scientists have found genistein to support the efficiacy of Cabazitaxel which is used for the treatment of hormone-refractory prostate cancer.
Pomegranate - Pomegranate extracts or rather its ingredients, i.e. ellagic acid, caffeic acid, luteolin and punicic acic, have been shown to inhibit the proliferation and induce apoptosis in prostate cancer cells (NCI. 2013).
Figure 1: If you look at the actual increase in apoptotic cancer cells in response to the pomegranate treatment, it is obvious that some patients (e.g. #53) benefited more than others (Pantuck et al. 2006)
A clinical trial by Pantuck et al. (2006) was also able to show that the time it takes for the PSA levels, an albeit debatable marker of prostate cancer risk, to double decreased significantly, when the subjects, men with rising PSA after surgery or radiotherapy, were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Unfortunately, a more recent study by Stenner-Liewen et al. (2013) could not confirm these effects.
Brassica vegetables (cruciferous vegetables) - While general vegetable intake is already associated with a -39% reduced risk of developing extraprostatic prostate cancer (cancer, eating tons of cruciferous vegetable, it was the intake of broccoli and cauliflower that made the biggest impact in a 2007 study by Kirsh et al.
Even if they don't protect you from prostate cancer broccoli & co will inhibit myostatin and could help you to grow more muscle... well, at least theoretically, you know about the difference between the petri dish and the real world, so don't expect monster gains | more.
As it is usually the case the evidence is yet ambiguous. In a 2002 review of the evidence, Kristal, et al. found that of the six studies they could clearly interpret, only three reported statistically significant reduced risks (P < 0.05), while one reported a borderline significant reduced risk (P = 0.06). Against that background Verhoeven et al. are right, when they say: " Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general" (Verhoeven. 1996).
More recently, Joseph et al. found that the existing differences in the epidemiological data may be due to genetic polymorphisms due to which only men with a certain genetic polymorphisms in glutathione S-transferases M1 and T1 will benefit from eating tons of cruciferous veggies (Joseph. 2004).
Green tea - Green tea is good for everything, right? Well unless it's not loaded with toxic molecules (see previous SuppVersity article) this may in fact be right. Convincing evidence from human trials is albeit scarce. What we do have are rodent studies like the ones that were conducted with TRAMP mice, which model closely mirrors the pathogenesis of human prostate cancer.
In these mice EGCG, one of the main catechins in green tea, decreased the proliferation of prostate cancer cells and reduced the PSA levels. Scientists believe that these effects are mainly mediated by the effects EGCG has on the growth promoting proteins ERK1/2. Unfortunately, the same rodent studies also suggest that it is probably too late for many of you to start drinking green tea, now, because said beneficial effects are only observed in young, not in old TRAMP mice (Donald. 2012).
Coffee is for the ladies, too! Studies show significantly reduced risks of breast cancer with 5+ cups of coffee. Tee and cacao help, as well | more
Coffee - Obviously I am biased, when it comes to coffee. I still hope you believe me when I say that drinking 5+ cups of coffee per day has been associated with significantly reduced risk of prostate cancer in what is probably the most large-scale meta-analysis of the topic today.
In their meta-analsis of 12 peer-reviewed case-control studies, Lu et al. calculated a 4% risk reduction for Europeans who consumed five or more cups of coffee and Americans who consumed 4 or more regular cups of coffee (equ. to approximately 400-500mg of caffeine). Moreover, the scientist found "a significant inverse association in all categories of prostate cancer except Gleason <7 grade" in both the "fixed-effects model" and the "random-effects model" (Lu. 2014).
Wilson et al. also report an inverse association between coffee consumption and the incidence of highly malignant prostate cancer (Wilson. 2013). This means that drinking coffee is not only going to reduce your overall risk of developing prostate and other cancers (Geybels. 2013), it will also increase your chance that in the unfortunate case you still develop cancer, it's going to be a benign and treatable form of prostate cancer.
Lignans (e.g. from flaxseed) - While many of you will probably know them as "bad anti-androgens", there is little doubt that lignans from flax and other foodstuff inhibit cancer growth. What is particularly interesting about these agents is that they don't work via the "regular" NF-kappaB pathway but inhibit the expression of the vascular endothelial growth favtor (VEGF; cf. Azrad. 2013).
Lycopene - It's the bright red carotene and carotenoid pigment and phytochemical that gives tomatoes and other red fruits and vegetables, such as red carrots, watermelons, gac, and papayas, although not in strawberries, red bell peppers, or cherries their color.
Based on the currently available evidence it appears to help not just with prostate, but also with pancreatic, intestinal and lung cancer (Giovannucci. 1999). In that, it makes a particularly effective adjunct to classic cancer therapy (Tang. 2011).
Figure 2: Prostate cancer risk w/ high vs. low intakes of the given antioxidants according to XRCC1 genotype (Goodman. 2006)
Unfortunately, the data is ambigious... as usual. Unlike for other agents, it does yet appear as if scientists have already identified a certain gene, i.e. XRCC1, which appears to determine whether you do or do not benefit from the consumption of increased amounts of tomato lycopene (Goodman. 2006).
In view of the fact that certain genotypes actually increase their prostate cancer risk specifically if they are consuming both, a high amount of lycopene and vitamin E (alpha-tocopherol), the latest Cochrane Review on the protective effects of lycopene against prostate cancer considers the evidence for "preliminary" and "insufficient" (Ilic. 2011).
Fish oil / omega-3 - In spite of the fact that the media jumped at the finding of the SELECT trial (learn more) that claimed that selenium would be bad, while a high fish consumption or rather a high amount of omega-3s in the blood would protect you against prostate cancer, a close re-analysis of the data you can read up on at the website of the Life Extension Foundation indicates that this was all media hype.
With a de facto difference of only 0.18% the difference was... well, you'd say a joke, scientists would say "within the margin of statistical error" and thus by no means significant. If you take an even closer look at the data, it would even seem as if omega-3 fatty acids would increase the risk of prostate cancer.
Resveratrol - If you look at the existing evidence you will be surprised to find studies that indicate that resveratrol increases (Klink. 2013) and studies that show that it inhibits prostate cancer growth (Iguchi. 2012; Kai. 2011).
Again, it took a closer look at the data and another experiment to find out what really was going on: a dose-dependent effect with increased risk with low and decreased risk with high doses of resveratrol (Benitez. 2007). Bad news: With the current low biovailable oral resveratrol preparations you're likely to end up in the "increased risk" resveratrol exposure zone.
Selenium - While I have mentioned it in the introduction already, it's certainly worth taking a closer look at what selenium is actually supposed to do.
In their 2011 review of the literature, Rizky Abdulah et al. didn't just highlight the many different molecular pathways, by which selenium could protect you from developing cancer, they also point out that the type of selenium supplement used could be of critical importance with respect to the success of your efforts to avoid the development of cancer. In that,...
In rodents selenium acts as corrosion inhibitor in the brain | learn more
"[...] methylselenol is believed to be the critical metabolite in selenium chemoprevention. Since methylselenol is highly reactive, methylselenol precursors such as Semet and Se-mSC are important both in in vitro and in vivo experiments. Semet and Se-mSC conversion to methylselenol, however, requires enzymatic conversion by the enzyme β-lyase, which is 800 times less prevalent in human tissues than in mouse tissues.
This may explain why the results of Semet and Se-mSC anticancer studies in humans were not as impressive as in vivo experiments. Although researchers have now turned to other Se compounds such as mSeA, which do not need enzymatic conversion to methylselenol, or selenite, which does not need to be converted to methylselenol for its anticancer properties, more substantial research on selenium compound metabolism in human tissues is necessary." (Abdulah. 2011)
In other words, as of now, we don't know which form of selenium we actually have to use in human trials to generate similar impressive results as they have been observed in rodents.
And as if that wasn't already "bad" enough, a meta-analysis of intervention studies by Hurst et al. (2012) indicates that there is a very narrow "band" of serum concentrations, where selenium is actually good for you! When your selenium level passes 170 ng/ml the tumor-protective effect disappears and - worst case scenario - your risk increases. So remember: More does certainly not help more!
Silibin (from milk thistle) - You probably think of milk thistle as a "liver supplement". In fact, its main active constituent will yet also reduce the efficacy of osteoclast cytokines and reduce the concentration of RANKL-ligands. Thus it will regulate the NF-κB und AP1 levels in cells and inhibit the proliferation, invasion and migration of metastatic prostate cancer (Ting. 2011; Chen. 2012)
Vitamin D - Believe it or not: There are things vitamin D3 cannot do! One of this things is to protect you prostate cancer. That's the prerogative of active vitamin D aka calciferol. In rodent studies and studies on human cell lines calciferol and multiple analogs of active vitamin D have shown to be promising drugs for prostate cancer protection, though (Tokar. 2005).
Underestimated Vitamin D Sources: Eggs, Chicken, Pork, Fish & Dairy Contain Ready-Made 25OHD | more
Since simply popping tons of vitamin D3 is (luckily) without effect on the levels of calciferol (otherwise you would run the risk of being calcified from the currently prevalent abuse of vitamin D3 supplements), using vitamin D3 is less effective, but not useless.
In 2010, for example, Woo et al. observed that the time it took for the PSA levels of prostate cancer patients to double was significantly reduced, when the subjects received 2,000 IU of vitamin D3 per day (Woo. 2005) - an effect of which previous in vitro studies suggest that it could be due to the local conversion of D3 to active vitamin D in prostate cancer cells (Tokar. 2005).
Vitamin E - Needless to say that vitamin E has gotten a bad rep ever since scientists observed an increased risk when they gave the subjects of the SELECT trial vitamin E (learn more). Still, as long as you stay away from "classic" vitamin E and buy one of the still expensive tocotrienol supplements (or eat red palm oil), you can expect an anti-proliferative effect of the vitamins E (Conte. 2004; Srivastava. 2006)
It's never too late to make a change! In September 2005, researchers from the University of California-San Francisco pub- lished a study that shows that intensive lifestyle changes (i.e. changin the way you eat, the amount of exercise you get, etc.) may affect the progression of prostate cancer in a highly beneficial way (Ornish. 2005) - with PSA reductions of -4%, reduced glucose levels (-70%!) improved blood lipids and higher, not lower testosterone levels.
Bottom line: While all of the above supplements and food constituents will help, nothing beats a healthy lifestyle with a balanced whole foods diet, stress control and regular exercise.
Overweight (+20% risk for BMI >25.38, already), gaining 5-10% weight after your 20s (+30%; Putnam. 2000), being self-employed (+170%) and thus probably stressed, having a family history of prostate cancer (father +140%, brother +420%), being a "former drinker" (beer +20%, wine +20%) or a current liquor drinker (+40%) and consuming more than 96g of alcohol per week (+50%), on the other hand, will - for most of the variables unnecessarily - increase your prostate cancer risk (Andersson. 1996) | Comment on FB!
References:
Abdulah, Rizky, et al. "Molecular targets of selenium in prostate cancer prevention (Review)." International journal of oncology 39.2 (2011): 301-309.
Andersson, Swen-Olof, et al. "Lifestyle factors and prostate cancer risk: a case-control study in Sweden." Cancer Epidemiology Biomarkers & Prevention 5.7 (1996): 509-513.
Azrad, Maria, et al. "Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer." Journal of medicinal food 16.4 (2013): 357-360.
Benitez, Dixan A., et al. "Mechanisms Involved in Resveratrol‐Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer—Derived Cell Lines." Journal of andrology 28.2 (2007): 282-293.
Chen, Rongxin, et al. "The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection." Annals of surgical oncology 19.3 (2012): 375-384.
Chiyomaru, Takeshi, et al. "Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer." PloS one 8.3 (2013): e58929.
Conte, Carmela, et al. "γ‐Tocotrienol Metabolism and Antiproliferative Effect in Prostate Cancer Cells." Annals of the New York Academy of Sciences 1031.1 (2004): 391-394.
Donald, J. L. "Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer." Molecular BioSystems 6.10 (2010): 1911-1916.
Geybels, Milan S., et al. "Coffee and tea consumption in relation to prostate cancer prognosis." Cancer Causes & Control 24.11 (2013): 1947-1954.
Giovannucci, Edward. "Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature." Journal of the National Cancer Institute 91.4 (1999): 317-331.
Guo H, Xu YM, Ye ZQ, Yu JH, Hu XY. "Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor." Pharmazie 68.6 (2013):431-4.
Hurst, Rachel, et al. "Selenium and prostate cancer: systematic review and meta-analysis." The American journal of clinical nutrition 96.1 (2012): 111-122.
Iguchi, Kazuhiro, et al. "Antiandrogenic activity of resveratrol analogs in prostate cancer LNCaP cells." Journal of andrology 33.6 (2012): 1208-1215.
Joseph, Michael A., et al. "Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk." Nutrition and cancer 50.2 (2004): 206-213.
Kai, Li, and Anait S. Levenson. "Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells." Anticancer research 31.10 (2011): 3323-3330.
Kirsh, Victoria A., et al. "Prospective study of fruit and vegetable intake and risk of prostate cancer." Journal of the National Cancer Institute 99.15 (2007): 1200-1209.
Klink, Joseph C., et al. "Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell‐line specific manner, through paradoxical effects on oncogenic pathways." The Prostate 73.7 (2013): 754-762.
Kristal, Alan R., et al. "Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk." Journal of the National Cancer Institute 106.3 (2014): djt456.
Lu, Yu, et al. "Coffee consumption and prostate cancer risk: an updated meta-analysis." Cancer Causes & Control 25.5 (2014): 591-604.
Merkle, W. "Prostatakarzinomprophylaxe durch Nahrungsergänzungsmittel." Der Urologe (2014): 1-7.
Ornish, Dean, et al. "Intensive lifestyle changes may affect the progression of prostate cancer." The Journal of urology 174.3 (2005): 1065-1070.
Pantuck, Allan J., et al. "Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer." Clinical Cancer Research 12.13 (2006): 4018-4026.
Putnam, Shannon D., et al. "Lifestyle and anthropometric risk factors for prostate cancer in a cohort of Iowa men." Annals of epidemiology 10.6 (2000): 361-369.
Stenner-Liewen, Frank, et al. "Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer-Results of a Phase IIb Randomized Controlled Trial." Journal of Cancer 4.7 (2013): 597.
Srivastava, Janmejai K., and Sanjay Gupta. "Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells." Biochemical and biophysical research communications 346.2 (2006): 447-453.
Tang, Yaxiong, et al. "Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels." Neoplasia 13.2 (2011): 108-119.
Ting, Harold, Gagan Deep, and Rajesh Agarwal. "Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer." The AAPS journal 15.3 (2013): 707-716.
Tokar, Erik J., and Mukta M. Webber. "Chemoprevention of prostate cancer by cholecalciferol (vitamin D3): 25-hydroxylase (CYP27A1) in human prostate epithelial cells." Clinical & experimental metastasis 22.3 (2005): 265-273.
Verhoeven, Dorette T., et al. "Epidemiological studies on brassica vegetables and cancer risk." Cancer Epidemiology Biomarkers & Prevention 5.9 (1996): 733-748.
Wilson, Kathryn M., et al. "Coffee and risk of prostate cancer incidence and mortality in the Cancer of the Prostate in Sweden Study." Cancer Causes & Control 24.8 (2013): 1575-1581.
Woo, Tony Choon Seng, et al. "Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy." Nutrition and cancer 51.1 (2005): 32-36.
Image 1: If you wanted to get the tocotrienol levels a producer of respective supplements says are "required", you would have to eat at least 200g palm fruits a day. Alternatively, you can resort to 4kg of oats, if you like those better... What? you are wondering that you are not dead by now? After so many years of tocotrienol deficiency from not getting your 4kg of oats?
The long lists of pathologies related to vitamin E deficiency include, among others, all sorts of degenerative diseases from ataxia over general muscle degeneration to degeneration of sperm and subsequent infertility. But despite the fact that there is a pretty substantial amount of evidence that would suggest that a diet rich in vitamin E could not just prevent the aforementioned pathologies, but would also protect us from many of the currently prevalent ailments of western society such as obesity and coronary vascular disease (Mishra. 2003; Rimm. 1993), respective trials with dietary supplements usually show no, or even negative effects. I have already addressed a couple of reasons why the benefits of dietary vitamin E intake often cannot be replicated with supplements in previous posts. The most significant one, probably is the absence of the "right" mixture and ratio of alpha-, beta-, gamma- and delta-tocopherols and, as an emerging contributer, the total absence of tocotrienols in the vast majority of vitamin E supplements and almost 99.9% of the pertinent trials.
What are tocotrienols? And what do they do?
I could now rant about the structural differences between the two, with the tocotrienols being an unsaturated variety of the tocopherols with a isoprenoid side chain, but I guess it is enough to know that due to differences in their molecular structure, they also differ in their effects on the human body, of which you may already have apprehended that their cholesterol lowering effects were the first to attract the attention from researchers (Qureshi. 1986). Within the last 26 years researchers from all around the world have identified additional health benefits, the most prominent of which are...
The purpose of today's SuppVersity article is yet not so much to compile the most extensive list of potential, purported or demonstrated benefits of tocotrienols, the major dietary sources of which are (Kobayashi. 1975; Tan. 2011)
human breast milk (!) [though this is probably no major source for you ;-]
but rather to take a look at an intriguing chart of the various molecular targets (Aggarwal. 2010) and discuss the implications:
Figure 1: Molecular targets (left) and proteins that directly interact with tocotrienols (right; adapted from Aggarwal. 2010)
As you can see without even looking really close at the above graphic, the number of those targets is vast. Another thing you should see right away is that the effect of the tocotrienols is mostly inhibitory (red ovals in the left) and include a couple of old foes, such as:
the inflammatory cytokines & transcription factors: IL-1, IL-6, TNF-alpha, nf-kappabeta, IL-8 (probably involved in auto-immune reactions), PF-A4 (increases platelet aggregation and thus thrombosis risk)
factors involved in angiogenesis and cardiocascular disease: VEGF (vascular growth factor, involved in CVD) and its receptor VEGF-r, VCAM-1 (increases adhesion of immune cells to the endothelial wall)
kinases involved in the cell cycle and apoptotic regulators: CDK's, PKC, pERK, etc. & survivin, IAP-1 & 2 etc., but also telomerase, which are all involved in the proliferation of cancer
enzymes involved in inflammatory processes: eNOS, iNOS, COX-2, etc.
On the upregulatory side of things, we have
enzymes from the CYP cascade, which are among other involved in the clearance of estrogen, and other hormone like substances and the metabolism of drugs,
MAPK and JNK, which exert anti-catabolic effects on muscle tissue, or
GPX and SOD, two of the major enzymes involved in the antioxidant defenses
Now, if we take a look at all these, you may remember that low COX-2 levels have only recently been identified with profound overtraining (cf. "Overtraining inflammation insufficient repair"), that AKT (not mentioned above, but in figure 1) is one of the driving forces of skeletal muscle anabolism and telomerase, extends cell life in general, not just in cancer cells. Which brings us back to the issue of ...
...how much anti-oxidants do we actually need?
Figure 2: Total tocopherol and tocotrienol content of high vitamin E foods / oils (top) and tocopherol ratios (bottom) , data based on Whittle. 1967 and Slover. 1971
Or, in this particular case, how much tocotrienols are still beneficial? Neither I, nor anybody else knows the exact answer to this question. And against this fact, the recommendations I came across on the website of a major producer of respective supplements, which state that you would need
80g of palm oilen (cooking oil),
160g of rice bran oil,
3kg of barley,
1.5kg of wheatgerm, or
4kg of oats
to (I quote) "achieve the required [my emphasis] level of tocotrienols" should tell any reasonable person that those "required" levels (~150mg) are probably required to generate the target revenue of the said company, yet probably not required for you or any other human being to thrive.
Do not stack one more, but take one out!
Instead of adding another overpriced (and probably overdosed) tocotrienol supplement to your regimen, it is thus probably wiser to simply drop any superflous and potentially harmful alpha-tocopherol only supplements which do would offset the alpha- to gamma- and delta- tocopherol ratio (this could potentially be ameliorated by taking a natural blend) and limit the total tocopherol intake to reasonable levels, as the latter has also been shown to hamper the absorption and retention of tocotrienols (Ikeda. 2003). In this context it is also noteworthy that Ping Tou Gee writes in a 2011 paper with the aptly chosen title "Unleashing the untold and misunderstood observations on vitamin E" that this fact alone would suggest that "there is a need to review critically on the dietary reference intakes recommendations" for alpha tocopherol (α-T). His bold statement that
[i]t is not known whether α-T is still essential to humans in long terms, α-T3 [alpha tocotrienol] diet appeared to produce healthy rats over five generations.
is yet probably an attribution to Palm Nutraceuticals Sdn. Bhd. (which is not the aforementioned company which wants to force-feed you either their supplements or 2 cups of rice bran oil), of which he states in the acknowledgments that he thanks them "for permission to publish this paper" and further evidence for how pathetic parts of the research in the medical field is - awful this science business, isn't it?
References:
Aggarwal BB, Sundaram C, Prasad S, Kannappan R. Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol. 2010 Dec 1;80(11):1613-31. Epub 2010 Aug 7.
Ahmad NS, Khalid BA, Luke DA, Ima Nirwana S. Tocotrienol offers better protection than tocopherol from free radical-induced damage of rat bone. Clin Exp Pharmacol Physiol 2005;32:761–770
Gee PT. Unleashing the untold and misunderstood observations on vitamin E. Genes Nutr. 2011 Feb;6(1):5-16. Epub 2010 Jul 20.
Ikeda S, Tohyama T, Yoshimura H, Hamamura K, Abe K, Yamashita K. Dietary alpha-tocopherol decreases alpha-tocotrienol but not gamma-tocotrienol concentration in rats. J Nutr. 2003 Feb;133(2):428-34.
Kato A, Yamaoka M, Tanaka A, Komiyama Ka, Umezawa I. Physiological effect of tocotrienol. J Japan Oil Chem Soc (Yukugaku) 1985;34:375–376.
Khanna S, Roy S, Ryu H, Bahadduri P, Swaan PW, Ratan RR, et al. Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J Biol Chem 2003;278:43508–43515.
Kobayashi H, Kanno C, Yamauchi K, Tsugo T. Identification of alpha-, beta-, gamma-, and delta- tocopherols and their contents in human milk. Biochim Biophys Acta 1975;380:282–290.
Kuhad A, Chopra K. Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci 2009;84:296–301.
Lee SP, Mar GY, Ng LT. Effects of tocotrienol-rich fraction on exercise endurance capacity and oxidative stress in forced swimming rats. Eur J Appl Physiol 2009;107:587–595.
Mishra GD, Malik NS, Paul AA, Wadsworth ME, Bolton-Smith C. Childhood and adult dietary vitamin E intake and cardiovascular risk factors in mid-life in the 1946 British Birth Cohort. Eur J Clin Nutr. 2003 Nov;57(11):1418-25.
Newaz MA, Nawal NN. Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens 1999;21:1297–1313.
Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S, Shneker B, Ganesh K, Phillips G, More JL, Sarkar A, Kirkpatrick R, Elkhammas EA, Klatte E, Miller M, Firstenberg MS, Chiocca EA, Nesaretnam K, Sen CK. Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients. J Nutr. 2012 Mar;142(3):513-9. Epub 2012 Feb 1.
Qureshi AA, Burger WC, Peterson DM, Elson CE. The structure of an inhibitor of cholesterol biosynthesis isolated from barley. J Biol Chem. 1986 Aug 15;261(23):10544-50.
Qureshi AA, Karpen CW, Qureshi N, Papasian CJ, Morrison DC, Folts JD. Tocotrienols-induced inhibition of platelet thrombus formation and platelet aggregation in stenosed canine coronary arteries. Lipids Health Dis. 2011 Apr 14;10:58.
Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993 May 20;328(20):1450-6.
Slover HT. Tocopherols in foods and fats. Lipids. 1971 May;6(5):291-6.
Sundram K, Khor HT, Ong AS, Pathmanathan R. Effect of dietary palm oils on mammary carcinogenesis in female rats induced by 7,12-dimethylbenz(a)anthracene. Cancer Res 1989;49:1447–1451
Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Oikawa S, Miyazawa T. delta-Tocotrienol suppresses VEGF induced angiogenesis whereas alpha-tocopherol does not. J Agric Food Chem 2009;57:8696–8704.
Tan B. Tocotrienols: The New Vitamin E. Spacedoc.net. http://www.spacedoc.com/tocotrienols
Weng-Yew W, Selvaduray KR, Ming CH, Nesaretnam K. Suppression of tumor growth by palm tocotrienols via the attenuation of angiogenesis. Nutr Cancer 2009;61:367–373.
Weng-Yew W, Brown L. Nutrapharmacology of tocotrienols for metabolic syndrome. Curr Pharm Des. 2011;17(21):2206-14.
Whittle KJ, Pennock JF. The examination of tocopherols by two-dimensional thin-layer chromatography and subsequent colorimetric determination. Analyst.1967 Jul;92(96):423-30.
Yoshikawa S, Morinobu T, Hamamura K, Hirahara F, Iwamoto T, Tamai H. The effect of gamma-tocopherol administration on alpha-tocopherol levels and metabolism in humans. Eur J Clin Nutr. 2005 Aug;59(8):900-5.
Yu FL, Gapor A, Bender W. Evidence for the preventive effect of the polyunsaturated phytolside chain in tocotrienols on 17beta-estradiol epoxidation. Cancer Detect Prev. 2005;29(4):383-8.
Some butter on top of the broccoli would allow for the assimilation of the absorption of the 101.6μg vitamin K 623IU vitamin A (various).
There are a handful of very basic questions in nutrition science, no one appears to have an answer to. One of these questions, which is directly related to the well-known fact that the vitamins A, D, E & K are "lipid soluble". This means that they are "solved" and thus made absorbable by fats and oils. The general assumption is thus that the vitamins A, i.e. the retinol and carotenoids, all forms of vitamin D, the tocopherols and -trienols (vitamins E) and the two major forms of vitamin K, i.e. phylloquinone (K1) and menaquinone (K2) will only be absorbed, if you consume them with a sufficient amount of dietary fat. Now, the questions obviously are (a) is this correct and (b) how much is sufficient.
Is there a rule of thumb? Well, I guess if there was one, it would be to consume 5-10g of low PUFA fats with every meal to maximize the absorption of fat-soluble vitamins. Needless to say, that this does not imply that you'd have to start adding olive oil to your post-workout shake ;-)
In view of the fact that the answers to (a) and be are not necessarily identical for all four vitamins of interest, it appears sensible to tackle them one after the other.
A
Starting with vitamin A and the various forms of carotenoids, we can already confirm that (a), i.e. the assumption that we need dietary fats to optimally absorb vitamin A is correct. As Karin van het Hof and her colleagues point out, the "amount of dietary fat required to ensure carotenoid absorption [does yet] seem low (∼3–5 g per meal), although it depends on the physicochemical characteristics of the carotenoids ingested." (van het Hof. 2000) In spite of the fact that 5g of fat are not exactly much, the classic uncooked vegetarian orthorexic salad often comes with a total of only 5g of fat of which 95% remain at the bottom of the salad bowl. If that sounds like your favorite dish, you should be aware that you are risking that all the good beta- and other carotenoids in the salad will pass right through.
Red Palm Oil is an excellent carotene source that comes with tons of fat for optimal absorption | learn more
With carotenes you should keep in mind that they have individual and "vitamin A"-related effects that occur after their conversion to retinol and the uptake of the latter through the lymphatic system in the gut. For this to take place the presence of a couple of ~5g of fat (Jayarajan. 2013) in the intestinal lumen is paramount importance. Even more than preformed vitamin A, carotenes do thus rely on the presence of dietary fat in your meals to be optimally converted (Goodman. 1966) and absorbed.
Figure 1: Changes in hepatic vitamin A (retinol) and carotenoid stores in gerbils after 14 days on high fat (30%) vs. low fat (10%) diet (Deming. 2000)
In that, the concomitant presence of both dietary fat and carotenoids in a meal is a necessary prerequisite for the absorption of vitamin A, also because the fatty acids will trigger the conversion of of beta-carotene into vitamin A and its subsequent absorption via the lymphatic system (Ribaya‐Mercado. 2002). It is thus not surprising that animal studies by Lakshman et al. (1996) and Deming et al. (2000; see Figure 1) suggest that low fat diet can lead to a depletion of the vitamin A tissue stores even if the serum levels remain constant. The amount of fiber in the diet, on the other, has no influence the absorption of vitamin A (Mills. 2009).
Interestingly enough, the provision of the fat blocker Orlistat reduces the absorption of vitamin A only insignificantly, as a 1996 paper by Angela T. Melia, Susan G. Koss‐Twardy, and Jianguo Zhi would suggest (Melia. 1996).
E
Which takes us right to vitamin E, the absoprtion which is - in spite of being "blocked" by the fat blocker orlistat (Melia. 1996) - less susceptible to the absence of dietary fat than you may think. Annet JC Roodenburg, Rianne Leenen, Karin H van het Hof, Jan A Weststrate, and Lilian BM Tijburg do in fact argue that the optimal intake of vitamin E requires only "a limited amount" of dietary fat (Roodenburg. 2000).
Figure 2: Vitamin E serum levels after 7 days on control (low fat, 3g) or high(er) fat (36g) diet with and without supplemental vitamin E (Roodenburg. 2000)
As you can see in Figure 2. A minimum intake of only 3g per day was sufficient to keep the vitamin E levels stable. The short study period of 7-days (each) and the absence of measures of tissue concentration of vitamin E do yet reduce the practical relevance of the data, Roodenburg et al. present in their Y2k paper in the American Journal of Clinical Nutrition.
The PUFA advantage: Aside from the issue of serum vs. tissue levels, there is yet another experimentally verified fat vitamin E and fat carotenoid interactions we should take into consideration, when we are talking about "optimizing" our dietary vitamin E supply; and that's the type of fat we consume: Dietary fats with increased ratio of unsaturated to saturated fatty acids enhance absorption of carotenoid and vitamin E by increasing both efficiency of micellarization and lipoprotein secretion (Chitchumroonchokchai. 2010).
If you take a look at the high prevalence of vitamin E dieficiency among the fat (and PUFA) "loving", or at least eating, majority of Americans, it does yet become obvious that a lack of dietary fat is not just theoretically, but also practically not exactly the #1 reason you may become deficient in tocopherols and -trienols. That the latter is an increased demand due to chronic inflammation and the (over-)consumption of exactly those PUFAs that come with a shitload of vitamin E in nature, for a reason would yet be a topic for another SuppVersity article and thus something we will skip to fast forward to ...
K
...Vitamin K, obviously. Vitamin K is a relative newcomer to the public's understanding of the alphabet soup. Aside from being it a good tool to rip customers vitamin K, or rather K1 (plant sources) and K2 (animal sources) are thus also the only fat soluble vitamins not everyone knows. The fact that the amount of phylloquinone (K1) that makes it into your blood stream is ~70% reduced if you eat your spinach without fat (Gijsbers. 1996).
And if we take the results researchers from the Gifu University School of Medicine present in a 1996 paper in the Journal of Pharmacological Sciences, as a reference, the amount of fat you need to optimally absorb your K2 (menaquinones), is not exactly low.
Figure 3: For optimal absorption of K2, there has got to be a huge amount of fat in the meal - but who wonders. K2 comes with a high amount of fat (Uematsu. 1996)
Uematsu et al. had to supply their subjects, who consumed otherwise identical test meals with 8.8, 20.0 and 34.9g of fat in them with the maximal (i.e. 35g) of fat before the K2 absorption maxed out. In that the total area under the curve did not really differ between those subjects who consumed the K2 before and those who took it immediately after the test meal.
That's a pity, 'cause a high intake of vitamin K (menaquinone from animal sources) has been associated with a 27% reduced risk of developing heart disease (Geleijnse. 2004), an ailment of which many still believe that it was brought about by the fat they need to optimally absorb their vitamin K.
D
For vitamin D, our last "V" on the list, things look differently. For one, everybody knows about this miracle vitamin and for two, it may be "fat soluble", but the amount of fat that's required to optimally absorb it turned out to be much lower than previously thought (see "A Fat D-Ficiency! Do You Really Need More Vitamin D or Simply More Fatty Foods? Study Shows, Even 50.000 IU of Vitamin D3 Useless, When You Ingest It Without Fat. " | read more).
Actually you could argue that it's not fat, but cholesterol that should be essential for optimal D levels. It's not necessary to absorb supplements you should not be taking, but rather as a raw material that's used to produce vitamin D in the skin, once the latter is exposed to the sun. The allegedly logical assumption that statins which lower the production of endogenous (=your body's own) cholesterol would lower vitamin D levels, however, has been refuted in study investigating the effects of fluvastatin and rosuvastatin, of which the latter actually increased the 25-OHD levels (probably due to anti-inflammatory effects and a reduced use of vitamin D as an acute phase reactant | learn more)
In fact, Niramitmahapanya et al. found in 2011 that it's not necessarily a high amount, but rather the right type of fat that determines if and how much of the vitamin D you take in capsule form or find in comparably low amounts in your foods that determines how much of the vitamin D actually makes it into your bloodstream:
"The change in plasma 25OHD (nanograms per milliliter) during vitamin D supplementation was positively associated with MUFA, (β = 0.94; P = 0.016), negatively associated with PUFA, (β = −0.93; P = 0.038), and positively associated with the MUFA/PUFA ratio (β = 6.46; P = 0.014)."
In plain English this means, that the "good" seed and vegetable oils with their high PUFA content will effectively inhibit the absorption of vitamin D - an observation that adds to the many reasons the modern sedentary, sun-avoiding, sun-screen using, soybean oil (MUFA:PUFA = 0.4) guzzling American is low in or quasi devoid of vitamin D.
Figure 4: 25(OH)D levels of 30 healthy men and women after ingestion of 50.000IU vitamin D3 supplement in conjunction with a normal or low fat breakfast (Raimundo. 2011)
Against that background it's not surprising that you will not find a conclusive answer to the question how much fat you actually need. In a study that used a fatty meal with soybean oil in it, the effect would be totally different from one in which the subjects consumed meals that were made with sunflower oil, an oil with a MUFA:PUFA ratio >1. In view of the results Gnadinger et al present in a recent appear it does still seem appropriate to consume at least some fat alongside your vitamin D supplements. As far as the food-borne vitamin D is concerned, you don't have to worry, anyways. Foods that are high in D3 usually come with all the fat you need to absorb it.
How much fat, exactly you would need to make the most of dietary and supplemental vitamin D, on the other hand, is still not known. The previously mentioned data from the study by Raimondo et al. (see Figure 4, to the right) I wrote about in "A Fat D-Ficiency" is obviously still valid. The extremely high amount of vitamin D (50,000IU!) could yet require a correspondingly high amount of fat to be optimally absorbed and the fact that the fat in the study came from a "vegetable margarine" with an undisclosed ratio of MUFA:PUFA does not make the real-world effects any more predictable.
So what do I need to optimally absorb my "fat soluble" vitamins?
Vitamin A & carotenes require relatively high amounts of fat for optimal absorption.
Vitamin D absorption benefits from additional fat in the diet. While we don't know the optimal amount, we do know the optimal type: A high MUFA, low PUFA fat (the effects of saturated fat are unknown, but I gather they will be positive, as well).
Vitamin E requires only minimal amounts of fat (~3g) for optima absorption.
Vitamin K appears to be most fat hungry. The more fat you have in a meal, the better it is absorbed. If you supplement, always take the pills with your highest fat meal in the day.
Bottom line: If you take a look at the natural sources, it should be obvious. The fat soluble vitamins are meant to be consumed with fat... well, not really. Carotenes (pre-vitamin A), one of those vitamins for which the presence of dietary fat in a meal is most important do not necessarily come with their own "absorb me better"-portion of fat. Your carrots, pepper, and other high carotene veggies and fruits do thus require a butter, olive oil or cream topic not just to be absorbed, but - more importantly - to get converted to retinol aka "active vitamin A".
Vitamin E, on the other hand, requires much lower amounts of fat to be absorbed than many of you may have thought. In fact, you could argue that good vitamin E sources are not high in fat to facilitate the absorption of vitamin A, but rather the other way around: Soybean oil (my absolute favorite poison ;-) is high in vitamin E to make sure that whoever consumes it does not die immediately from the pro-inflammatory omega-6 load it contains.
Which takes us right to the 18-20g and 12-15g of PUFAs the average US man and woman consume on a daily basis (Kris-Etherton. 2000) and their negative impact on the absorption of the already low amounts of dietary vitamin D in a diet that rarely contains the optimal amount of 35g of fat in meal that actually has a significant amount of vitamin K the absorption of which would be improved by the presence of this allegedly unhealthy and fattening macronutrient.
References:
Chitchumroonchokchai, Chureeporn, et al. "Dietary fats with increased ratio of unsaturated to saturated fatty acids enhance absorption of carotenoid and vitamin E by increasing both efficiency of micellarization and lipoprotein secretion." FASEB J 24 (2010): 539-3.
Deming, Denise M., et al. "Amount of dietary fat and type of soluble fiber independently modulate postabsorptive conversion of β-carotene to vitamin A in Mongolian gerbils." The Journal of nutrition 130.11 (2000): 2789-2796.
Geleijnse, Johanna M., et al. "Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study." The Journal of nutrition 134.11 (2004): 3100-3105.
Gijsbers, Birgit LMG, Kon-Siong G. Jie, and Cees Vermeer. "Effect of food composition on vitamin K absorption in human volunteers." British Journal of Nutrition 76.02 (1996): 223-229.
Goodman, Dew S., et al. "The intestinal absorption and metabolism of vitamin A and beta-carotene in man." Journal of Clinical Investigation 45.10 (1966): 1615.
Jayarajan, P., Vinodini Reddy, and M. Mohanram. "Effect of dietary fat on absorption of β carotene from green leafy vegetables in children." Indian journal of medical research 137.5 (2013).
Kris-Etherton, P. M., et al. "Polyunsaturated fatty acids in the food chain in the United States." The American journal of clinical nutrition 71.1 (2000): 179S-188S.
Lakshman, M. R., et al. "The effects of dietary taurocholate, fat, protein, and carbohydrate on the distribution and fate of dietary β‐carotene in ferrets." (1996): 49-61.
Melia, Angela T., Susan G. Koss‐Twardy, and Jianguo Zhi. "The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers." The Journal of Clinical Pharmacology 36.7 (1996): 647-653.
van het Hof, Karin H., et al. "Dietary factors that affect the bioavailability of carotenoids." The Journal of nutrition 130.3 (2000): 503-506.
Raimundo, Fabiana Viegas, et al. "Effect of high-versus low-fat meal on serum 25-hydroxyvitamin D levels after a single oral dose of vitamin D: a single-blind, parallel, randomized trial." International journal of endocrinology 2011 (2011).
Ribaya‐Mercado, Judy D. "Influence of Dietary Fat on β‐Carotene Absorption and Bioconversion into Vitamin A." Nutrition reviews 60.4 (2002): 104-110.
Roodenburg, Annet JC, et al. "Amount of fat in the diet affects bioavailability of lutein esters but not of α-carotene, β-carotene, and vitamin E in humans." The American journal of clinical nutrition 71.5 (2000): 1187-1193.
Uematsu, Toshihiko, et al. "Effect of dietary fat content on oral bioavailability of menatetrenone in humans." Journal of pharmaceutical sciences 85.9 (1996): 1012-1016.
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 substances
Tocotrienols - 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!?
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.
