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 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!?

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.

Biotin, Folic Acid & B12 & Glucose Management | Part IX of the "There is More To Glucose Control Than Low Carb" - Series: Are Extra "B"s Good for Non-Diabetics as Well?

There is evidence for beneficial effects of B7 and B12 in Alzheimer's. Yet although the this disease is often called "diabetes of the brain" the evidence that B7 and B12 would do anything but ameliorate the damage due to increased blood glucose levels and decreases insulin sensitivity is non-existent.

I guess, you will remember that my analysis of the role of thiamin (B1), riboflavin (B2), pantothenic acid (B5) and pyridoxin (B6) revealed... well, what did it reveal? Not much, aside from the fact that the importance of these B-vitamins in glucose management is probably overrated. For niacin, the fifth B-vitamin I have covered in this series, thing looked much different: At high doses niacin (as nicotinic acid) will have profound effects on your glucose metablism and whether those are beneficial or bad for you may eventually depend on the timing of your niacin supplements.

In today's installment of the "There is More to Glucose Control Than Low Carb"-Series, we will tackle the rest of the B-vitamin pack to find out whether we have to add biotin (B7), folic acid (B9) and cobalamin (B12) to our list of "non-carbohydrate nutrients" with profound effects on blood glucose management.

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

In view of the fact that B12 is one of the shining stars on the supplement firmament and its role in mitochondrial health, it appears to be logical to assume that a couple of additional cobolamine pills (or even injections) will also help you maintain / improve your insulin sensitivity. If we take a look at one of the standard lists of symptoms that occur with low B12 levels, we will yet find

"Pernicious anemia (numbness and tingling in hands and feet / nerve damage), shortness of breath, severe fatigue, birth defects, dementia, confusion, poor memory, depression, reduced WBCs and platelet formation, loss of appetite, weight loss, sore tongue, headaches, and nausea,"

but not a single hint that low vitamin B12 levels could compromise your blood glucose management. And still, even if there is no direct link between vitamin B12 and diabetes, there is more than one good reason for diabetics to take cobalamine supplements:

• 

  Glucose management is not among the standard functions of B7 and B12.

  improvements in diabetic neuropathy (Yaqub. 1992; Sun. 2005)
• increased risk of gestational diabetes with low B12 levels (Krishnaveni. 2009)
• epigenetic programing that increases type II diabetes risk in the offspring of B12 deficient mouse and man (Yajnik. 2008; Deshmukh. 2013) 
• diabetes induced cobalamine depletion (Solomon. 2011)
• the central role of B12 in the methylaction cycle and its role in glucose management (Finer. 2013)

On the other hand, many of the results of previous studies are of questionable value in view of the fact that serum vitamin B12 do not adequately reflecting vitamin B12 status in patients with type 2 diabetes (Obeid. 2013). It is thus no wonder that peer-reviewed evidence that would confirm any beneficial effects of B12 supplementation on glucose management is absent.

B12 injections & L-5-MTHF supplements? For both, folic acid and methylcobalamine the provision of adequate intake levels is essential for overall health. And with both you will find people who have a hard time meeting their biological requirement due to digestive (B12; esp. elderly individuals) and genetic defects (no conversion of folic acid to fale). For these people, but not for Mr. and Mrs. Average Joe it may thus be worth spending the extra bucks on hydroxcobalamine injections and L-5-Methyltetrahydrofolate (L-5-MTHF) supplements, even if they won't have immediate beneficial effects on their blood glucose management.

The same lack of conclusive evidence for it's direct contribution to / beneficial effects on glucose control can be found for folic acid, as well. Just like B12 it appears to help to buffer the neurological side effects of insulin resistance and reduce increased homocysteine levels of which some, but not all scientists believe that they would increase your risk of heart disease.
 
If it were not for biotin which has a whole host of peer-reviewed studies to support its ability to improve the insulin sensitivity of diabetic and pre-diabetic animals (Reddi. 1988) and human beings (McCarty, 1999).

Figure 1: Both blood lipids and glucose management of the diabetic subjects improved w/ chromium picolinate (600µg Cr) +biotin (2 mg) in study by Cesar Albarracin et al. (2008)

As it was the case in the study by Albarracin et al. Figure 1 is based on, biotin is often co-administered with chromium picolinate. As you can see with quite some success and the same increase in insulin release that will also occur in healthy individuals on high dose chromium supplements (learn more).

Beware: High dose biotin supplements are not necessarily good for healthy individuals!

And even though there is evidence that biotin will also have beneficial effects on glucose management, when it is administered (again in high doses of 1-2g) without chromium to patients with diet-induced insulin resistance & diabetes (Koutsikos. 1996; Zhang. 1996) and patients with type I diabetes (Hemmati. 2013), I have to warn you: If you don't have blood glucose issues to begin with, taking several grams of biotin per day could do more harm than good.

Figure 2: Changes in glucose (fasting glucose and insulin levels) and lipid management triglyceride and total cholesterol) after 4 weeks on 3x5mg/day biotine in healthy and diabetic individuals (Báez-Saldaña. 2004)

In the study that generated the data in Figure 2 (Báez-Saldaña. 2004), biotin failed to produce any (not even insignificant) improvements in glucose management in the diabetic subjects and led to allegedly non-significant increases in blood glucose and insulin levels in the healthy study participants (see Figure 2). With 3x5mg/day the dosage was yet exorbitantly high. It's thus not surprising that the effects were similarly detrimental as those of the high dose chromium regimen by the means of which Masharani et al. messed with the insulin sensitivity of their likewise healthy subjects a previously discussed study from 2012 (read more).

Biotin, rather for blood lipid than blood glucose management: Rather than for blood glucose, you may want to use biotin supplements for blood lipid management. As Asdrúbal Aguilera-Méndez and Cristina Fernández-Mejía argue in a 2012 paper in the scientific journal BioFactors, biotin works by increasing c-AMP and AMPK - both well, known mechanism that are triggered by lipid-lowering herbs and meds, as well. Larrieta et al. even argue that pharmacological doses of biotin will reduce the expression of lipogenic genes - genes which control, among other things, the conversion of glucose to triglycerides and the storage of the latter in the adipose organ. In a way, this mechanism could also be responsible for the increase in serum glucose Báez-Saldaña et al. observed in their high dose biotin supplementation study.

Well, the beneficial effects on blood lipids have been observed by  Marshall et al., as well (Marshall. 1979) - at only 0.9mg/day. In their study of the "effects of biotin on lipids and other constituents of plasma of healthy men and women", they observed (a) a significant negative correlation between plasma and biotin levels and (b) a reduction in plasma lipids in response to biotin supplementation that depended not on the dosing, but on the baseline levels, meaning that volunteers who initially had elevated levels of lipids showed greater lipid reductions than those who had normal levels of lipids.

Similar benefits occur at 1x5mg as they were administered by Revilla-Monsalve et al. to 18 diabetic and 15 normo-glycemic individuals. In contrast to the 3x5mg overdose in the previously cited study, though, the "[b]iotin treatment had no significant effects on cholesterol, glucose and insulin in either the diabetic or nondiabetic subjects." (Revilla-Monsalve. 2006).

So how much do you take? If you are asking me, the answer would be none, and that despite the fact that over here in Germany "food" is not as intoxicated... ah, I mean "fortified" with additional folic acid.

If you insist on supplementing stick to 400mcg (600mcg, when pregnant) of folic acid and max 500mg of methylcobolamine (highly orally bioavailable form of B12) per day. That's plenty.

And biotin? Well <500mcg per day probably won't hurt you.

So what? All useless? In the end, "useless" is probably a bit too strong of a word. There is no doubt that folic acid and B12 supplements won't be able to reverse diabetes, but they can ameliorate the side effects and are essential for women who want to make sure they don't pass your own pre-diabetes on to your offspring.

Biotin on the other hand, appears to have a place in the treatment of acute diabetes. For the average insulin sensitive SuppVersity reader who does not have elevated triglyceride levels or other blood lipid issue, high amounts of supplemental biotin (anything beyond 1mg per day chronically and 5mg per day in the short run) could even have similarly detrimental health effects as their comrades in crime, the highly popular chromium picolinate supplements.

References:

• Albarracin, Cesar A., et al. "Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes." Diabetes/metabolism research and reviews 24.1 (2008): 41-51.
• Báez-Saldaña, Armida, et al. "Effects of biotin on pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and markers for glucose and lipid homeostasis in type 2 diabetic patients and nondiabetic subjects." The American journal of clinical nutrition 79.2 (2004): 238-243.
• Deshmukh, Urmila, Prachi Katre, and Chittaranjan S. Yajnik. "Influence of maternal vitamin B12 and folate on growth and insulin resistance in the offspring." (2013): 145-156.
• Finer, S., et al. "The role of the one‐carbon cycle in the developmental origins of Type 2 diabetes and obesity." Diabetic Medicine (2013).
• Hemmati, Mitra, Homa Babaei, and Mohammadreza Abdolsalehei. "Survey of the Effect of Biotin on Glycemic Control and Plasma Lipid Concentrations in Type 1 Diabetic Patients in Kermanshah in Iran (2008-2009)." Oman medical journal 28.3 (2013): 195.
• Koutsikos, Dimitris, et al. "Oral glucose tolerance test after high-dose iv biotin administration in normoglucemic hemodialysis patients." Renal failure 18.1 (1996): 131-137.
• Krishnaveni, G. V., et al. "Low plasma vitamin B12 in pregnancy is associated with gestational ‘diabesity’and later diabetes." Diabetologia 52.11 (2009): 2350-2358. 
• Larrieta, Elena, et al. "Pharmacological concentrations of biotin reduce serum triglycerides and the expression of lipogenic genes." European journal of pharmacology 644.1 (2010): 263-268.
• Marshall, M. W., et al. "Effects of biotin on lipids and other constituents of plasma of healthy men and women." Artery 7.4 (1979): 330-351.
• Masharani U, Gjerde C, McCoy S, Maddux BA, Hessler D, Goldfine ID, Youngren JF. Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity. BMC Endocr Disord. 2012 Nov 30;12(1):31. 
• McCarty, M. F. "High-dose biotin, an inducer of glucokinase expression, may synergize with chromium picolinate to enable a definitive nutritional therapy for type II diabetes." Medical hypotheses 52.5 (1999): 401-406.
• Obeid, Rima, et al. "Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes." Biochimie 95.5 (2013): 1056-1061.
• Reddi, Alluru, et al. "Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice." Life sciences 42.13 (1988): 1323-1330.
• Revilla-Monsalve, Cristina, et al. "Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in nondiabetic subjects with hypertriglyceridemia." Biomedicine & pharmacotherapy 60.4 (2006): 182-185.
• Solomon, Lawrence R. "Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment." Blood reviews 21.3 (2007): 113-130.
• Sun et al. "Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials."ACTA NEUROLOGICA TAIWANICA 14.2  (2005): 48-54.
• Yajnik, C. S., et al. "Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study." Diabetologia 51.1 (2008): 29-38.
• Yaqub, Basim A., Abdulaziz Siddique, and Riad Sulimani. "Effects of methylcobalamin on diabetic neuropathy." Clinical neurology and neurosurgery 94.2 (1992): 105-111. 
• Zhang, Hong, et al. "A high biotin diet improves the impaired glucose tolerance of long-term spontaneously hyperglycemic rats with non-insulin-dependent diabetes mellitus." Journal of nutritional science and vitaminology 42.6 (1996): 517-526.

Vitamin A (Retinol) & Glucose Management | Part VIII of the "There is More To Glucose Control Than Low Carb"- Series. Plus: Retinol's Effects on Pancreas, Liver, Muscle and Fat

Vitamin A is not exactly known for being an anti-diabetes vitamin. If anything people will associate it with skin health... and SuppVersity Readers probably with anti-cellulite treatments | learn more

In the previous installments of this series I have addressed many of the "usual suspects" everyone associates with non-carbohydrate dependent improvements in blood glucose management. In today's installment of this series I will now take a look at an important vitamin of which only few would expect that it is in any way involved in glucose management: Vitamin A - real, pre-formed retinoic acid, not beta-carotene.

In view of the misleading news about the "involvement" of retinol binding proteins in the etiology of the diabesity epidemic and the bullocks about the negative effects of vitamin A on vitamin D, the vast majority of health junkies all over the web will probably associate high vitamin A intakes with insulin resistance, not -sensitivity.

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

Against that background it's funny that both human type II diabetics, as well as one of the most commonly used rodent models of type II diabetes, the streptozotocin-induced diabetic rat, show an impaired metabolic availability of vitamin A (Basu. 1989; Tuitoek. 1996).

As the scientists from the University of Alberta point out, the increased hepatic and the decreased plasma and retina vitamin A levels clearly "suggest a defect in the transport of the vitamin from the liver" - a defect of which it's not unlikely that it is the cause of the previously mentioned increases in retinol binding protein 4 (RBP4) that are so characteristic of the average overweight type II diabetic (Cho. 2006). Whether this problem can be resolved by the provision of supplemental vitamin A is albeit highly controversial.

Vitamin A is involved in body fat control (Bonet. 2003)

Low vitamin A status favors increases in fat deposition: The important effects of vitamin A on the proliferation of pre-adipocytes and adipose tissue morphology in general are often overlooked. In 2003, Bonet et al. were yet able to show that low levels of vitamin A are not just associated with insulin resistance and type II diabetes, they will also favor the deposition of body fat, which would otherwise be blunted by the negative effects of retinol on the activity of the body fat storage initiator C/EBPb (Bonet. 2003).

Basu & Basualdo, for example, argue that "subnormal vitamin A status in poorly controlled diabetic subjects may not respond to vitamin A supplementation". Even worse, if the vitamin A is not released into circulation and transported to the target tissue, where it appears to be dearly needed, it may "increase [the] load in the liver", eventually "leading to hepatoxicity" (Basu. 1997); and the increased levels of CRP and blood lipids Farhangi et al. observed in obese women in response to the ingestion of albeit exorbitant amounts of vitamin A (25.000IU/day; Farhangi. 2013).

Table 1: Overview of correlation coefficients of vitamin A and weight, BMI, tricep skinfold thickness (TSF), subscapular skinfold thickness (SST), total, HDL and LDL cholesterol, as well as triglycerides (Viroonudomphol. 2003)

In view of the fact that Viroonudomphol et al. have observed a negative correlation between weight, BMI, skinfold thickness, LDL & total cholesterol, triglycerides and hip circumference, on the one hand, and the serum retinol levels of overweight and obese subjects it is in fact a pity that a simple 10,000IU vitamin A supplement could do more harm than good to overweight and obese individuals with a messed up vitamin A metabolism (Viroonudomphol. 2003).

There are other things vitamin A can day for the diabetic patient -- It can promote wound healing, for example (Seifter. 1981). It can (at least in rodent trials) reduce the expression of resistin (Felipe. 2004), which is associated with increased levels of "bad" oxidized LDL cholesterol and is in itself a biomarker for the risk of heart failure (Salam. 2013; Takeishi. 2013). When it's administered with zinc at a daily dose of 25,000IU retinol can the improve serum apoprotein A-I, apoprotein B and the apoprotein B/apoprotein A-I ratio in patients with type I diabetes (Shidfar. 2013) and may thus directly reduce their heart disease risk.

Whether the potential side effects will yet occur in subjects, in whom the elevated glucose levels are adequately controlled is yet questionable. The results a group of researchers from the Ankara University presented in 2002 article in the peer-reviewed scientific journal Cell Biochemistry and Function, for example, would suggest that the addition of supplemental vitamin A to the standard insulin therapy in type II diabetes will not just help to keep the exuberant glucose levels in check, it may also blunt the oxidative reactions in diabetic heart and may thus "provide more benefits than use of either agent alone in the treatment of the "general characteristics of diabetes and the maintenance of antioxidant defense of diabetic heart and thus in the reduction of peroxidative stress-induced cardiac injury" (Zobalı. 2002).

Figure 1: Vitamin A affects several key steps in glucose metabolism (highlighted by dark arrows Berdainer. 2001)

In the pancreas, vitamin A deficiency leads to defects in both glucagon and glucose-stimulated insulin secretion (Chertow. 1987 & 1994), of which the latter can be restored with retinol palmitate supplements.

As Berdainer et al. point out, "glucose-stimulated insulin secretion is a complex process that requires the metabolism of glucose and the mitochondrial production of ATP" (Berdanier. 2001) - a process, in which the rate limiting enzymes that are regulated by retinoic acid (see Figure 1).

The vitamin A metabolite all-trans-retinoic acid is a real "anti-metabolic syndrome"-agent (Bonet. 2012)

An increase in skeletal muscle fatty acid oxidation is another not "glucose"-related benefit of vitamin A supplementation. As of now this effect has only been confirmed in rodent studies, where the administration of the potent vitamin A metabolite all-trans-retinoic acid (ATRA) lead to a 3.5x increase in PPAR-delta expression and corresponding increases in skeletal muscle fatty acid oxidation (Amengual. 2008) and increases in fatty acid oxidation in the liver (Amengual. 2010).

In conjunction with its ability to "brown" white fat cells and thus turn fat stores into fat furnaces (Mercader. 2006), the increases in skeletal muscle fatty oxidation will obviously also have secondary anti-diabetic effects (warning: ATRA is significantly more toxic than vitamin A and liposomal delivery reduces, but does not abolish these effects; cf. Ozpolat. 2003).

Glucokinase, which is thought to act as a glucose sensor, regulating insulin secretion and liver glucose uptake, is one of the enzymes regulated by retinoic acid in both the beta cell and the liver. Against that background it's no wonder that the systemic vitamin A deficiency that's so characteristic of insulin resistant and diabetic individuals worsens the already impaired glucose control.

Figure 2: In the absence of adequate vitamin A levels mature (myocyte) and immature (myoblast) muscle cells won't react to insulin by an increase in GLUT-4 expression and corresponding glucose uptake (Sleeman. 1995)

In conjunction with a reduction of the retinoic acid induced up-regulation of insulin-stimulated glucose transport via GLUT 4 in muscle cells (see Figure 2), the loss (?) of vitamin A that occurs at the onset of type II diabetes (Lu. 2000) is thus part of the often-cited vicious cycle of diabesity.

In that, the negative association between vitamin A and non-alcoholic fatty liver disease José Botella-Carretero et al. observed in morbidly obese subjects just another component of the under-appreciated involvement of vitamin A in the etiology of diabetes (Botella-Carretero. 2010) - an involvement of which we yet don't know whether it's causally, corellative or both.

Just as an aside: Vitamin A will also increase the expression of the master anti-oxidant glutathione in muscle tissue and promote the survival skeletal muscle precursor cells (El Haddad. 2012). It is necessary to preserve protein (Esteban-Pretel. 2010). And protects the muscle from the catabolic effects of corticosteroid overload (Aubry. 2009). Not glucose related, but not bad either, right?

Bottom line: There is little doubt that low vitamin A levels will contribute to the development of insulin resistance - both directly, by its negative effect on the pancreatic insulin production, and its insulin-induced glucose uptake in skeletal muscle tissues, as well as indirectly by its pro-obesogenic effects, and reductions in fatty acid oxidation and brown adipose tissue activity.

What is questionable, though, is whether the provision of supplemental vitamin A will have any direct or indirect beneficial effects on glucose metabolism in the average lean vitamin A sufficient individual and/or vitamin A deficient (pre-)diabetics. Against that background I would recommend to keep an eye on an adequate dietary vitamin A intake from eggs, dairy, butter, meat, fish and the occasional serving of liver and / or supplemental retinyl palmitate (e.g. 10,000 IU; 2-3x per week).

References:

• Amengual, Jaume, et al. "Retinoic acid treatment enhances lipid oxidation and inhibits lipid biosynthesis capacities in the liver of mice." Cellular Physiology and Biochemistry 25.6 (2010): 657-666. 
• Aubry, Evelyne M., and Alex Odermatt. "Retinoic acid reduces glucocorticoid sensitivity in C2C12 myotubes by decreasing 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor activities." Endocrinology 150.6 (2009): 2700-2708.
• Basu, T. K., W. J. Tze, and J. Leichter. "Serum vitamin A and retinol-binding protein in patients with insulin-dependent diabetes mellitus." The American journal of clinical nutrition 50.2 (1989): 329-331.
• Basu, Tapan K., and Carlotta Basualdo. "Vitamin A homeostasis and diabetes mellitus." Nutrition 13.9 (1997): 804-806.
• Berdanier, Carolyn D., et al. "Role of vitamin A in mitochondrial gene expression." Diabetes research and clinical practice 54 (2001): S11-S27.
• Bonet, M. L., et al. "Vitamin A and the regulation of fat reserves." Cellular and Molecular Life Sciences CMLS 60.7 (2003): 1311-1321. 
• Bonet, M. Luisa, Joan Ribot, and Andreu Palou. "Lipid metabolism in mammalian tissues and its control by retinoic acid." Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1821.1 (2012): 177-189.
• Botella-Carretero, José I., et al. "Retinol and α-tocopherol in morbid obesity and nonalcoholic fatty liver disease." Obesity surgery 20.1 (2010): 69-76.
• Chertow, B. S., et al. "Effects of vitamin A deficiency and repletion on rat insulin secretion in vivo and in vitro from isolated islets." Journal of clinical Investigation 79.1 (1987): 163.
• Chertow, B. S., et al. "Effects of vitamin A deficiency and repletion on rat glucagon secretion." Pancreas 9.4 (1994): 475-484.
• Cho, Young Min, et al. "Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes." Diabetes care 29.11 (2006): 2457-2461. 
• El Haddad, Marina, et al. "Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival." Journal of cell science 125.24 (2012): 6147-6156.
• Esteban-Pretel, Guillermo, et al. "Vitamin A deficiency increases protein catabolism and induces urea cycle enzymes in rats." The Journal of nutrition 140.4 (2010): 792-798.
• Farhangi, Mahdieh Abbasalizad, et al. "Vitamin A supplementation, serum lipids, liver enzymes and C-reactive protein concentrations in obese women of reproductive age." Annals of clinical biochemistry 50.1 (2013): 25-30.
• Felipe, Francisco, et al. "Modulation of resistin expression by retinoic acid and vitamin A status." Diabetes 53.4 (2004): 882-889. 
• Lu, Jing, et al. "The metabolic availability of vitamin A is decreased at the onset of diabetes in BB rats." The Journal of nutrition 130.8 (2000): 1958-1962.
• Mercader, Josep, et al. "Remodeling of white adipose tissue after retinoic acid administration in mice." Endocrinology 147.11 (2006): 5325-5332.
• Ozpolat, Bulent, et al. "Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers." J Pharm Pharm Sci 6.2 (2003): 292-301.
• Salam, Gazbar, et al. "Relationship between Oxidized-LDL and Resistin Levels in Obese Diabetic Subjects." (2013).
• Seifter, E., et al. "Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A." Annals of surgery 194.1 (1981): 42. 
• Shidfar, Farzad, et al. "Effects of combination of zinc and vitamin A supplementation on serum fasting blood sugar, insulin, apoprotein B and apoprotein AI in patients with type I diabetes." International journal of food sciences and nutrition 61.2 (2010): 182-191.
• Sleeman, Mark W., et al. "Retinoic acid stimulates glucose transporter expression in L6 muscle cells." Molecular and cellular endocrinology 108.1 (1995): 161-167.
• Takeishi, Y. "Resistin Is a Novel Biomarker for a Risk of Heart Failure." J Cardiovasc Dis Diagn 1.122 (2013): 2.
• Tuitoek, P. J., et al. "Streptozotocin-induced diabetes in rats is associated with impaired metabolic availability of vitamin A (retinol)." British Journal of Nutrition 75.04 (1996): 615-622.
• Tungtrongchitr, Rungsunn, et al. "The relationships between anthropometric measurements, serum vitamin A and E concentrations and lipid profiles in overweight and obese subjects." Asia Pacific J Clin Nutr 12.1 (2003): 73-79.
• Zobalı, Fulya, et al. "Effects of vitamin A and insulin on the antioxidative state of diabetic rat heart: a comparison study with combination treatment." Cell biochemistry and function 20.2 (2002): 75-80.

Vitamin C & Glucose Management | Part VI of the "There is More To Glucose Control Than Carbohydrates"-Series. Plus: The Limits & Limitations to Oral Ascorbic Acid Supplements

Foods over pills! Not forks over knives ;)

Over the past weeks I have written so much about the anti-adaptational effects of ROS-scavengers that I probably don't have to mention the impressive (for some people shocking results) of the 2009 study by Ristow et al. with the telling title: "Antioxidants prevent health-promoting effects of physical exercise in humans" (Ristow. 2009) to underline that not everything is gold that comes in yellow packages and is labeled w/ vitamin C. Much contrary to the yellow, orange, red, green and blue natural vitamin C sources from the super- or farmers-market, by the way.

Before I get lost in the hormesis debate, I do yet want to adopt to a more general, non-exercise related perspective to check, if the impairment of exercise-induced improvements in insulin sensitivity is the only interaction between vitamin C and glucose metabolism.

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

And I guess I am not giving away too much if I tell you that there is a plethora of research on the effects of vitamin C in those whom we are about to call "Average Joes & Janes" in roughly 10 to 20 years - the obese diabetics.

In 1996, already,  Julie C. Will and her colleagues from the National Center for Chronic Diease Prevention and Health Promotion speculated that type II diabetics could have an increased requirement of vitmamin C (Will. 1996). And in fact, their detailed review of the contemporary literature, on the other hand, revealed that

"people with diabetes mellitus to have at least 30% lower circulating ascorbic acid concentrations than people without diabetes mellitus" (Will. 1996).

On the other hand, all efforts to increase glucose control (=lower the elevated blood glucose levels) by supplementation "had little impact on blood glucose concentrations." (Will. 1996)

Vitamin C to avoid collateral damage

This does not mean that the provision of extra vitamin C to diabetics was useless, though. By re-establishing an improved free-radical balance the extra ascorbic acid did reduce the levels of cellular sorbitol concentrations and ameliorated the overall increase in capillary fragility.

Overview of the vitamin C content of selected foods (CDC.gov)

Once and for all - Vitamin C is ascorbic acid - This does necessarily entail that it does not matter whether the guys who produced the pills you are popping claim to have gotten their raw material from kiwis, oranges, or your grandma's favorite saussages (yes, vitamin C is a commonly used preservative) - it will all have the same often overhyped effects on your health. If there was any way to actually produce "natural" vitamin C with certain "improved" effects on your health, it would be by combining it with other plant molecules you would usually find next to ascorbic acid in high vitamin C foods... and how do you do this? You simply eat your 100g of guava to make sure you covered your daily allowance for the next 5 days or pick any of the other foods in the table to the left.

Against that background it's not surprising that the latest review / meta-analysis of the use of antioxidant vitamin supplementation shows significant increases in endothelial function in non-obese subjects with type 2 diabetes mellitus:

Vitamin C is the "old vitamin D": For both scientists and laymen have long been confusing cause (increased inflammation) and effect (reduced ascorbic acid / 25OHD levels).

"Post-intervention standardized mean difference (SMD) in endothelial function did not reach statistical significance between groups (0.35; 95% confidence interval = −0.17, 0.88; P = 0.18). In subgroup analysis, post-intervention endothelial function was significantly improved by antioxidant vitamin supplementation in T2DM subgroups with body mass index (BMI) ≤ 29.45 kg m−2 (SMD = 1.02; P < 0.05), but not in T2DM subgroups with BMI > 29.45 kg m−2 (SMD = −0.07; P = 0.70)." (Montero. 2014)

With only 286 subjects in ten randomized controlled trials comparing antioxidant vitamin-supplemented and control groups being reviewed, we do yet have to be careful not to overestimate the results of this meta-analysis by scientists from the Avignon University, the Maastricht University Medical Centre and Cardiovascular Research Institute and, last but not least the Department of Internal Medicine at the Brigham & Women's Hospital in Boston (Montero. 2014).

Still, the fact that most studies reporting (often non-significant) benefits in fasting blood glucose (e.g. Vaksh. 2013 - 1,000mg vitamin C) have been conducted in labs with a low international reputation and published in journals with no or only minimal peer-reviewing does not exactly strengthen my confidence that vitamin C has any direct beneficial effects on glucose control in type II diabetics (this does not mean that it wouldn't be a good idea to use vitamin C as a means to reduce the cytotoxicity associated with hyperglycemia in prediabetes and type 2 diabetes; cf. Franke. 2013).

Direct effects of vitamin C supplementation on glucose control

Now, the chronic intake scenario in type II diabetics turned out to be quite disappointing, so let's turn to the purported benefits for the (still) normal folks. People like the older participants of a prospective study by Song et al. in which the researchers from the Harvard Medical School and other labs observed that the use of vitamin C and calcium supplements (see previous installment of this series on calcium) was associated with significantly lower risk of diabetes (-9% for vitamin C, but -15% for calcium; the use of a multivitamin was associated with non-significant increases in diabetes risk; Song. 2011)

The skinny on vitamin C - some general remarks: Vitamin C is an essential dietary nutrient for the biosynthesis of collagen and a co-factor in the biosynthesis of catecholamines, L-carnitine, cholesterol, amino acids, and some peptide hormones. The lack of vitamin C causes scurvy, a pathological condition leading to blood vessel fragility and connective tissue damage due to failure in producing collagen, and, finally, to death as result of a general collapse (Grosso. 2013).

Outside of the "older individual" scenario reported benefits are yet rare. In contrast to the consumption of obviously vitamin C containing foods like green leafy vegetables, which is associated with a 14% reduction in risk of type 2 diabetes (Carter. 2010), the evidence for benefits in glucose management and reductions in type II diabetes risk from supplemental vitamin C in healthy, young individuals is scarce to non-existent and the presence of these effects a "‘nutraceutical’ industry-driven myth which should be abandoned." It is, and that's true beyond the context of women's health, "a myth in need of urgent burial" (Talaulikar. 2011).

And Talaulikar and Manyonda, the two scientists from the St George's Hospital NHS Trust in London, who demand the abandonment of this ‘nutraceutical’ industry-driven myth and ceasing the massive and expensive clinical trials of vitamins C and E provide a list of convincing arguments to explain why the "vigorous antioxidant activity in the test tube" does not translate into real world ealth benefits, when vitamin C and other vitamins are packaged in pure form in a capsule and swallowed in large quantities:

• Loss of natural synergists in food: The antioxidants in fruit and vegetables may be tightly bound within the tough fibrous material of these foodstuffs and may exert their antioxidant activity not in the blood or tissues but in the gastrointestinal tract where free radicals are constantly generated from food (Halliwell. 2008). Supplements, on the other hand, are probably digested too quickly to replicate the effect. 
• Limited increase in serum vitamin C levels from oral supplement: Elegant studies by Lean et al. (Lean. 2003) showed that oxidative stress plays a crucial role in oophorectomy-induced osteoporosis in mice, and that vitamin C will prevent the development of osteoporosis when given intraperitoneally at a dose of 1 mmol/kg twice a day. The human equivalent of the vitamin C dose they used is 20 g per day. The equivalent serum levels of vitamin C cannot be achieved if the supplement is given by the oral route, since there is an upper limit for absorption of vitamin C of about 500 mg, which is why this is normally the highest dose given. Any more vitamin C stays in the gut and may cause osmotic diarrhoea and other gastrointestinal upset (Institute of Medicine - US. 2000). 

The last factor, i.e. the oral bioavailability or, more precisely the effect of supplemental vitamin C on serum ascrobic acid levels is a commonly overlooked factor which could in fact be similarly important as the previously mentioned lack of synergists.

Figure 1: May. plasma vitamin C concentrations (mmol/in healthy subjcets after oral or intravenous administration of vitamin C (large graph); the small graph shows the time-response w/ oral supplementation (Padayatty. 2004).

As you can see in Figure 1 oral supplements cannot increase the plasma vitamin C concentrations into the mmol/l range. Vitamin C concentrations as they have been reported to be cytotoxic to various malignant cell lines can thus not be achieved by via the oral route (Padayatty. 2001). It is thus not only very unlikely that you can "kill" cancer cells with tons of orally administered vitamin C. It could also put you at risk of an unwanted increase in pro-diabetic dehydroascorbic acid (oxidized = used vitamin C; cf. Patterson. 1950) and the corresponding negative consequences on glucose control.

Even if we discard reports by Podmore, et al. who warn that supplementing with more than 500mg of vitamin C will result in significant increases in pro-oxidant 8-oxoguanine and 8-oxoadenine concentrations and an increase in a potentially mutagenic lesions following high dose vitamin C supplementation (Podmore. 1998) or the copper-depleting effects of vitamin C (Lönnerdal. 1996), which could well be accelerated by and in turn accelerate the obesogenic effects of the standard western diet (Song. 2012), the mere inefficiency of high dose oral vitamin C supplements should be reason enough to stay away from doses in the multiple gram range. 

Figure 2: Glucose infusion rate (GIR) measured during a 180-min hyperinsu-linemic-euglycemic clamp for the Antioxidant group (A) and the Placebo group (B) after 16 weeks on 500mg vitamin C + 400IU vitamin E per day (Yfanti. 2011)

Before I close today's installment of the "There is More To Glucose Control Than Carbohydrates"-Series I do have to briefly get back to the potential negative effects of vitamin C for pro-athletes and wanna-be-athletes. While there is good evidence that the provision will blunt the long term adaptation, it's  not as if you would have to avoid a eating a cup of cherries before or after the workout, because their vitamin C content could hamper the post-exercise increase in insulin sensitivity.

As a SuppVersity reader you know that these acute effects, of which Christina Yfanti and her colleagues from the University of Copenhagen have been able to show that they are not blunted by the provision of 500mg of vitamin and 400IU of vitamin E over a 16(!) week period (see Figure 2).

Eventually, this conservation of the beneficial effects on glucose uptake in the presence of medium amounts of supplemental antioxidants is only logical: The training, a program consisting of intervals (intensity 75–91% Pmax and duration 60–80 min) and continuous biking (intensity 55–66% Pmax and duration 85–155 min) is after all more than intense enough to lead to the AMPK increasing decrease in ATP/ADP ratio which is responsible for the non-glucose and only partially insulin dependent increase in glucose uptake after a workout.

Three simple rules of reasonable vitamin C intake / supplementation.

Bottom line:  The current evidence appears to suggest that the ingestion of a total of 100-500mg of vitamin C and thus significantly more than the official US RDA (60mg) offers nothing but benefits - specifically if the lions-share of ascorbic acid comes from high vitamin C foods, like fruits and veggies.

The consumption of copious amounts of supplemental vitamin C (750mg+ per day), on the other hand, must be treated with caution. In spite of the fact that there is little evidence of vitamin C induced improvements in glucose management, there is plenty of evidence to support the notion that the extra vitamin C can ameliorate the collateral damage that occurs as a consequence of the increase in glucose levels in insulin resistant / diabetic individuals.

References:

• Domínguez-Perles, R., et al. "Brassica Foods as a Dietary Source of Vitamin C: A Review." Critical Reviews in Food Science and Nutrition just-accepted (2013).
• Franke, Silvia Isabel Rech, et al. "Vitamin C Intake Reduces the Cytotoxicity Associated with Hyperglycemia in Prediabetes and Type 2 Diabetes." BioMed research international 2013 (2013). 
• Grosso, Giuseppe, et al. "Effects of Vitamin C on health: a review of evidence." Frontiers in bioscience 18 (2013): 1017-29.
• Halliwell, Barry. "Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?." Archives of biochemistry and biophysics 476.2 (2008): 107-112.
• Institute of Medicine (US). Panel on Dietary Antioxidants, and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. National Academies Press, 2000. 
• Lönnerdal, B. "Bioavailability of copper." The American journal of clinical nutrition 63.5 (1996): 821S-829S.
• Montero, D., et al. "Effect of antioxidant vitamin supplementation on endothelial function in type 2 diabetes mellitus: a systematic review and meta‐analysis of randomized controlled trials." Obesity Reviews 15.2 (2014): 107-116. 
• Padayatty, Sebastian J., and Mark Levine. "New insights into the physiology and pharmacology of vitamin C." Canadian Medical Association Journal 164.3 (2001): 353-355.
• Padayatty, Sebastian J., et al. "Vitamin C pharmacokinetics: implications for oral and intravenous use." Annals of Internal Medicine 140.7 (2004): 533-537.
• Patterson, John W. "The diabetogenic effect of dehydroascorbic and dehydroisoascorbic acids." Journal of Biological Chemistry 188 (1950): 81-88.
• Ristow, Michael, et al. "Antioxidants prevent health-promoting effects of physical exercise in humans." Proceedings of the National Academy of Sciences 106.21 (2009): 8665-8670.
• Vaksh, Shreyasi, et al. "The Effect Of Vitamin-C Therapy On Hyperglycemia, Hyperlipidemia And Non High Density Lipoprotein Level In Type 2 Diabetes." Int. J. LifeSc, BT and Pharm. Res (2013): 290-295.
• Song, Yiqing, et al. "Multivitamins, individual vitamin and mineral supplements, and risk of diabetes among older US adults." Diabetes care 34.1 (2011): 108-114.
• Song, Ming, et al. "High fructose feeding induces copper deficiency in Sprague–Dawley rats: A novel mechanism for obesity related fatty liver." Journal of hepatology 56.2 (2012): 433-440.
• Talaulikar, Vikram Sinai, and Isaac T. Manyonda. "Vitamin C as an antioxidant supplement in women's health: a myth in need of urgent burial." European Journal of Obstetrics & Gynecology and Reproductive Biology 157.1 (2011): 10-13.
• Will, Julie C., and Tim Byers. "Does diabetes mellitus increase the requirement for vitamin C?" Nutrition reviews 54.7 (1996): 193-202. 
• Yfanti, Christina, et al. "Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training." American Journal of Physiology-Endocrinology and Metabolism 300.5 (2011): E761-E770.