SuppVersity Science Round Up Seconds: Wheat Gluten Hydrolysates Fail, Exposure to Air Pollutants During Workout Reduces Brain Benefits, Homocysteine, B-Vitamins, Cognitive Impairment and Mortality

Before the profound weight loss (A) you don't see any of the glucose sucking and fad burning brown fat depots (black spots in B) on the neck of the in (B) 'foermerly obese', now only 'overweight' subject (also take a look at how the visceral fat in the abdominal region in (A) is actually pushing the organs upwards; img Vijgen. 2012)

Those of you who have listened to yesterday's show will have noticed that despite its flow the number of things you can discuss in a 1h podcast is simply very limited, to say the least. This is also why these Friday posts are probably never going to be simple summaries of the SuppVersity Science Round Up of the day before. The same is true for today and still I decided not to use the allegedly lame logo I did for the first two installments, but provide you with some 'real science' evidence of the absence of brown adipose tissue on the obese and it's magical reappearance after shedding 100lbs+ subsequent to a gastric bypass operation, instead (see image on the right).

Assuming that you have no idea what this "evidence" is for, I would suspect that you missed the live show yesterday and also did not find the time to download and listen to the podcast, yet -- right? Well, you should either download and listen to the show now and digest the Seconds later, or you read the following paragraphs first and download the podcast later.

What is not an option, however, is to miss one or another - I mean you can hardly want to eat the seconds if you have not had the main dish yet... and after listening to the podcast, I cannot imagine you don't want at least some seconds. Apropos seconds, here are today's seconds...

• Wheat gluten hydrolysate is not the new goto protein supplement - certainly not for female distance runners and probably not for anyone else, either! These are the kinds of studies that really annoy me. Studies that start out with blatant statements like "WGH [Wheat gluten hydrolysate] has been reported to suppress post-exercise rises in serum creatine kinase in male distance runners" (Hirao. 2012).
  
  

  

  Figure 1: CK, AST, ALT response in the "success trial" with men. In women even the miniscule beneficial effect on CK was not there. No reason to even think about buying a gluten hydrolysate as you new go-to protein supplement with only 5.6g of leucine/100g (whey has 50% more) and almost no GSH replenishing cysteine in it (0.9g vs. 3g+ in whey, which is more than +200% more).

  Sentences like that make the null-results of the study they precede look like the exception to the rule and are still nothing but a concession to a bias (let's hope not due to the grant from Nisshin Pharma Inc. which was the manufacturer of the wheat gluten hydrolysate used in this study). A bias, due to which an isolated observation as the slightly blunted increase in CK is blown up as if a slightly lower CK level was what could turn a sedentary pencil pusher into the next Hussein Bolt (Aoki. 2012).
  
  So, even if you are not afraid of the evil in gluten (which I believe not everyone has to), I strongly caution against making the switch from a high EAA protein with ton's of GSH boosting cysteine in it like whey to a mediocre grain protein, which is a potential allergen and contains tons of glutamine your body will readily turn into glucose, once it passes through the portal veign into the liver (I bet a large part won't even make it into systemic circulation).
  
  And as far as the purported "gender difference" goes the study at hand tries to blame the null result on (Hiriao. 2012), I suspect that it is rather the indisputable difference between the long-distance running at a continuous pace the women in the study at hand did, versus the totally different strains the guys in the previous study were exposed to during a soccer training + mini-match, which made the difference.
• Working out next to a street takes away some of the beneficial cognitive effects due to ultrafine particulate matter (UFPM) exposure. "Working out in the fresh air will promote weight loss more than working out inside." You heard me state that in one of the previous installments of the SuppVersity Science Round Up on Super Human Radio. Now this is still correct and based on sientific evidence, but at least as far as the cognitive benefits are concerned, working out outside does also have its downsides - at least for those of you who live in the inner city area.
  
  

  

  You better watch what you breath while you run.

  During a 12-week program the researchers from the Universiteit Brussel, the Hasselt University and the Royal Military Academy measured the improvements in physical performance, changes in serum markers and corresponding ultrafine particulate matter (UFPM) concentrations in the enviromnent in which their 15 previously untrained subjects conducted their aerobic training program thrice a week (Bos. 2012). What Bos et al. found was that the UFPM levels were signfificantly higher in the urban compared to the rural environment and that the higher UFPM exposures correlated with increases in leukocyte counts (p = 0.02), neutrophil counts (p = 0.04), and eNO levels (p = 0.002) that were exclusively observed in the group that trained in the urban environment.
  
  With the latter being markers of inflammation which exert their effects systemically, i.e. not just in the lung or musculature of which you may be thinking now, but also in the brain, it is no wonder that
  

  "reaction times on the Stroop task improved in the rural group (p = 0.001), but not in the urban group" (Bos. 2012). 

  What's comforting, though, is that the physical fitness did increase to a similar extend in both arms of the study.
• Homocysteine levels, mortality, cognitive impairment and which nutrients can offer some protection. I am not sure about what your impression is, but for whatever reason homocystein seems to be 'out of vogue' -- probably no room for it on the research agenda with all the hype surrounding vitamin D. It used to be all the rage in CVD risk research and today's news item is actually ain't about cardiovascular health, either.
  
  What the researchers from China and Taiwan actually were interested in was the correlation of high and low homocysteine levels with cognitive impairment and the corresponding nutrient intakes. In that Xiu et al. paid particular attention to the "B-vitamins" and found the following correlations between the mortality, cognitive status, homocystein levels and nutrient intake of their 1412 study participants (Xiu. 2012):
  

  • 

    Figure 2: Unadjusted mortality in the four quartiles of homocysteine levels (top); mortality according to homocysteine levels in subjects with different degrees of cognitive impairment (based on Xiu. 2012)

    if you go by the unadjusted data in figure 2, it's plain obvious that the all-cause mortality increases linearly from one quartile to the other 
  • this relation between plasma homocysteine levels and all mortality remained statistically significant after adjustments for age, sex, smoking status, BMI, physical function and general health were made
  • of the general foods, the scientists assessed, only regular fish intake had a statistically significant effect on homocysteine levels, with higher intakes being associated with lower homocysteine levels
  • of the b-vitamins choline was the only one with a significant association with plasma homocysteine levels (suggested read "Old School Supplement Choline Could Save Your Live and Liver!") 
  • neither betaine, nor vitamin B1, B2, B3 or B6 intakes did show statistically significant correlations with plasma homocysteine (not even "borderline significant; p > 0.15 for all, most way hither)
  • of the plasma markers, folate showed a highly significant correlation with homocysteine (14.4 nmol/L in the lowest HCY and 8.70 nnmol/L in the highest HCY group)
  • PLP, the active form of vitamin B6, came in close second with 70.3 nmol/l in the lowest HCY quantile and only 44.4 nmol / l in the highest quantile.
  Now, if you consider the fact that higher intakes of B-vitamins are probably not doing much to lower homocysteine levels int he elderly (at least not dose-dependently, when they are already getting enough) oddity #1, another look at the data in figure 2 will reveal oddity #2: The surprisingly high mortality in the lowest homocysteine quartiles in the patients with severe cognitive decline - how come? I mean, with low homocysteine they should not be at risk of having severe cognitive decline, anyway - right?
  
  Actually if you follow this rationale you can almost answer the question yourself. If you have low homocysteine and severe cognitive decline, the severe cognitive decline can hardly be from high homocysteine levels, so it must have another obviously pathological reason, or as the scientists have it
  

  "The joint effects of the 2 variables [homocysteine and cognitive decline] were most pronounced with severe cognitive impairment where mortality HRs ranged from 5- to 18-fold across a wide range of homocysteine concentrations. The findings with hypohomocysteinemia provide some insight into what might be an optimal range for this analyte in peripheral blood and tissues. The low concentrations may be seen with severe illness and malnutrition, and our study population comprises the health-vulnerable aged. For these reasons, we adjusted these associations for BMI (using the World Health Organization chronic energy deficiency category of, 18.5 kg/m 2 ), and we excluded those who died in the first year of follow-up. The findings were unchanged. Because mortality among the very old may have skewed the joint effects, these are presented for those ≤75 years and over, but again with similar findings." (

  A sarcastic person would now probably say: "We all have to go some time!" and just wave his hands at these results. True! And I am the last to advice you to become over-anxious. Yet in the mean time it would appear prudent to make sure to get your homocysteine levels checked from time to time, not to forget that choline is a b-vitamin as well and not to fall for the idea that you cannot overdose on B-vitamins - I don't have to remind you of the negative effects, specifically folic acid supplementation can have on all sorts of cancer (e.g. breast cancer, where a high folic acid intake from foods and supplements is associated with a +30% risk of cancerous growth; cf. Kim. 2006).

In case you are looking for the post on "ammonia accumulation brain-fog, toxicity, liver 'pathologies' and workout performance", yeah it was on the list, but I decided it would be a shame to tackle that within a short two paragraph seconds items. Don't worry I am not going to forget about it, after all its in my humble opinion one of the main reasons the diets and workout regimen of the many ambitious physical culturists fail. If you are still looking for more and have not listened to the podcast, yet, this would be the right moment to download the file from the Super Human Radio Network server (click here to download), otherwise the latest short news on the SuppVersity Facebook Wall may offer some diversion ;-)

References:

• Aoki K, Kohmura Y, Suzuki Y, Koikawa N, Yoshimura M, Aoba Y, Fukushi N, Sakuraba K, Nagaoka I, Sawaki K. Post-training consumption of wheat gluten hydrolysate suppresses the delayed onset of muscle injury in soccer players. Exp Ther Med. 2012 Jun;3(6):969-972. Epub 2012 Apr 3.
• Bos I, De Boever P, Vanparijs J, Pattyn N, Panis LI, Meeusen R. Subclinical Effects of Aerobic Training in Urban Environment. Med Sci Sports Exerc. 2012 Oct 15.
• Cankurtaran M, Yesil Y, Kuyumcu ME, Oztürk ZA, Yavuz BB, Halil M, Ulger Z, Cankurtaran ES, Arıoğul S. Altered Levels of Homocysteine and Serum Natural Antioxidants Links Oxidative Damage to Alzheimer's Disease. J Alzheimers Dis. 2012 Oct 29.
• Guest PC, Urday S, Ma D, Stelzhammer V, Harris LW, Amess B, Pietsch S, Oheim C, Ozanne SE, Bahn S. Proteomic analysis of the maternal protein restriction rat model for schizophrenia: Identification of translational changes in hormonal signalling pathways and glutamate neurotransmission. Proteomics. 2012 Oct 16.
• Hirao T, Koikawa N, Aoki K, Sakuraba K, Shimmura Y, Suzuki Y, Sawaki K. Female distance runners show a different response to post-workout consumption of wheat gluten hydrolysate compared to their male counterparts. Exp Ther Med. 2012 Apr;3(4):641-644.
• Kim YI. Does a high folate intake increase the risk of breast cancer? Nutr Rev. 2006 Oct;64(10 Pt 1):468-75.
• Vijgen GH, Bouvy ND, Teule GJ, Brans B, Hoeks J, Schrauwen P, van Marken Lichtenbelt WD. Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab. 2012 Jul;97(7):E1229-33. Epub 2012 Apr 24.
• Xiu LL, Lee MS, Wahlqvist ML, Chia-Yu Chen R, Huang YC, Chen KJ, Li D. Low and high homocysteine are associated with mortality independent of B group vitamins but interactive with cognitive status in a free-living elderly cohort. Nutr Res. 2012. Ahead of print.

Which Micro- & Macronutrients Intakes Are Associated With High HDL Levels? Study Shows Magnesium & Folate Are, High Carbohydrate & Total Animal Fat Intakes Are Not!

The advantage of HDL is its stability that reduces the risk of plaque build-up in the intestinal wall, which is clogged by the remnants of oxidized LDL and causes heart disease & co.

First things first: We are not talking about "hard experimental evidence" as you could generate it in a randomized controlled trial in a metabolic ward. The data I am reporting today is from a cohort with 1,566 participants with extensive lipid phenotype data completed the Harvard Standardized Food Frequency Questionnaire to determine their daily micronutrient intake over the past year - an epidemiological study that used stepwise linear regression was used to separately evaluate the effects of dietary covariates on adjusted levels of HDL-C, HDL-2, HDL-3, and apoA1.

Interestingly, this is the first study with a quality data-set that determined the association between specific dietary micronutrients with HDL-C, HDL-2, HDL-3, and apoA1, and how these dietary associations differ across the various measures of HDL - not just one.

Learn more about HDL, cholesterol, heart health & co at the SuppVersity

Prohormones mess with your cholesterol.

Every other day fasting for your lipids

Dairy Protein Satiety Shoot-Out: Casein vs. Whey

Fish oil & oleic acid counter their ben. effects

Eggs increase cholesterol reverse transport

Does roasted coffee increase bad LDL?

To identify the HDL-promoters in the diet, the scientists use demographic and clinical variables in the base model. What they found was that numerous dietary intakes increased total HDL-C variance.
The results of their stepwise linear regression model in Table 1 indicate - probably for some people much surprisingly - that all alcohol intake levels were positively associated with HDL-C.

"In addition, magnesium, folate, and the saturated fat, myristic acid (14:0), were all positively and independently associated with HDL-C. Carbohydrate intake, iron, and % of fat derived from animal sources were each negatively additive for HDL-C." (Kim. 2014)

Similar effects from dietary intakes were observed for HDL-2, of which we know that it is decreased in women with rheumatoid arthritis (Arts. 2012) and individuals with other inflammatory diseases (including metabolic syndrom) and associated with a slightly higher reduction in acute myocardial infarction risk than "regular" HDL in several studies (Salonen. Salonen. 1991; Stampfer. 1991; Buring. 1992; Gaziano. 1993) for all alcohol intakes, magnesium, folate, and myristic acid (14:0), eicosapentaenoic acid (20:5, a ω-3 EPA), all of which were positively and independently associated with HDL-2 levels.

Table 1:  Best-fit model from stepwise linear regression predicting HDL-C levels using dietary intake data (Kim. 2014)

The opposite was the case for arachidonic acid (20:4, an ω-6 ARA), carbohydrate and iron intakes, which were both negatively associated with HDL-2 (see Table 1).

Don't forget to put things into perspective!

And just to make sure, I don't get angry emails from bulletproof coffee drinkers: Your coffee is fine, the content of the only "good" saturated fat, i.e. myristic acid, happens to be especially high coconut oil (41%; Sodamade. 2013) and relatively high in butter (12% independent of whether it's grass-fed or not; Couvreur. 2006) - surprised? Not really, I guess. As a SuppVersity reader you are by now aware that the bad reputation coconut oil and butter have for being mostly saturated fats is no longer supported by contemporary scientific evidence (Dias. 2014).

And with respect to the total animal fat intake - for the average Westerner that's a good measure of how much processed meat he / she eats, so I would not overrate the small negative association (1/80 of the one of having a ton of carbohydrates in your diet!) the scientists found in the study at hand.

Eggs are unquestionably and exception from the "animal fat" is bad for HDL rule | learn more.

Bottom line: With the exception of folate, which has previously not been reliably associated with increases in HDL, let alone speficic HDL subfraction, the improvements with alcohol, magnesium and EPA are not exactly news. The same is true for the decreases in response to increased intakes of (all) animal fat, arachidonic acid, carbohydrates and iron.

In the end, the study confirms what we already know: The way you eat (and train; see Leon. 2001) can directly affect the level of the heart-healthy HDL fractions in your blood.

One thing you should keep in mind, though, is that it's the ln = logarithmus of these macronutrients and micronutrients that's associated with increased / decreased HDL and its subfractions. This means that small changes are not really important. Things that would count are eating low carb vs. extreme high carb or eating no folate containing foods vs. a significant amount of these.

References:

• Arts, Elke, et al. "High-density lipoprotein cholesterol subfractions HDL2 and HDL3 are reduced in women with rheumatoid arthritis and may augment the cardiovascular risk of women with RA: a cross-sectional study." Arthritis Res Ther 14.3 (2012): R116.
• Buring, J. E., et al. "Decreased HDL2 and HDL3 cholesterol, Apo AI and Apo A-II, and increased risk of myocardial infarction." Circulation 85.1 (1992): 22-29.
• Couvreur, S., et al. "The linear relationship between the proportion of fresh grass in the cow diet, milk fatty acid composition, and butter properties." Journal of dairy science 89.6 (2006): 1956-1969.
• Dias, C. B., et al. "Saturated fat consumption may not be the main cause of increased blood lipid levels." Medical hypotheses 82.2 (2014): 187-195.
• Gaziano, J. Michael, et al. "Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction." New England Journal of Medicine 329.25 (1993): 1829-1834. 
• Kim et al. "Effects of dietary components on high-density lipoprotein measures in a cohort of 1,566 participants." Nutrition & Metabolism 2014, 11:44.
• Leon, ARTHUR S., and OTTO A. Sanchez. "Response of blood lipids to exercise training alone or combined with dietary intervention." Medicine and science in sports and exercise 33.6 Suppl (2001): S502-15.
• Salonen, Jukka T., et al. "HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men." Circulation 84.1 (1991): 129-139. 
• Sodamade, A¹, and O. S. Bolaji. "Fatty acids composition of three different vegetable oils (soybean oil, groundnut oil and coconut oil) by high-performance liquid chromatography." Chemistry and Materials Research 3.7 (2013): 26-29.
• Stampfer, Meir J., et al. "A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction." New England Journal of Medicine 325.6 (1991): 373-381.

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.