Stevia - More Than Super Sweet: More Scientific Evidence, More Potential Implications for Weight Loss & -Maintenance, Anti-Diabetic & -Autoimmune and Even Pro-Anabolic Effects

Image 1: Stevia is sweeter than sugar, healthier than sugar and could even help reverse some of the damage sugar may already have done to your pancreas.

I know that a few of you were almost furious, when I had the audacity to mention the case-report on the pro-cortisol effects of stevia in the On Short Notice post on Saturday, August 18, 2012; and though I did emphasize that this was most likely something like an allergic reaction and/or an issue with solvents, heavy metals (click here for data on heavy metals in stevia leaves; based on Das. 2012), or whatever else may have been in the specific stevia product the lady used; I suspect that you will like today's blogpost which is basically an update on the beneficial effects stevia could have on your overall and metabolic health, much better.

So what's the latest about stevia, then?

Previous studies have already hinted at the fact that the benefits of the use of stevia go well beyond a mere reduction in energy intake and the overall glucose load the average sweet tooth is exposing her- / himself to. Against that background, the results of a recent publication from the School of Pharmacy in Madhya  Pradesh in India are actually not really surprising.

Figure 1: Blood glucose response (mg/ml) to oral glucose load (left) and superoxide dismutase (SOD) levels in mice treated with 250mg/kg (HED: 20mg/kg; ~1.4-2.0g) stevia extract/day (right; data based on Sharma. 2012)

With most previous studies being conducted on isolated pancreatic islet cells in the petri dish, this is however one of the few studies, which in which the scientists were able to observe a robust in-vivo effect from the administration of no more than 250mg/kg of stevia extract (Herbocal) to alloxan-diabetic (this is a model of type II diabetes that is induced by the injection of the drug Alloxan aka 2,4,5,6-pyrimidinetetrone, an oxygenated pyrimidine derivative) and healthy rodents for 28days - with benefits for both, the sick (normalization of blood glucose and restoration of endogenous antioxidants) and the healthy animals (no drop of blood glucose to hypoglycemic levels and increases in SOD above baseline!)

Could stevia not just ameliorate, but actually "heal" diabetes?

Figure 2: It takes it's time but stevia appears to (fully?) restore pancreatic function!

What's also intriguing are the time-course and general trend of the beneficial effects on blood glucose levels in the diabetic group. If you take a closer look at the data in figure 2 you could even speculate that another four weeks later the blood glucose levels would have totally normalized! And if that were the case, this would mean that the steviosides and rebaudiosides, the active molecules in stevia extracts, could actually have the ability to restore or repair the pancreatic beta cells that have been destroyed by either years of high blood glucose (normal type II diabetics) or the assault of the toxic sugar equivalent alloxan (in the study at hand). and protect healthy individuals against future damage by increasing the endogenous antioxidant system (as can be seen by the allegedly non-significant, but probably still physiologically relevant increase in SOD in figure 1, right)

"But this won't work in humans, will it?"

The above is certainly a good question, but in view of the fact that the short term benefits (e.g. +40% increase in insulin response in type II diabetic with -18% reduced postprandial glucose AUV with 1g of stevia in Gregersen et al. 2004), of which the Hermansen group at the Aarhus University Hospital in Aarhus, Denmark, argues that they are based on the interaction of rebaudioside A (cf. table 1) with the ATP-sensitive K-channels of the pancreatic cells in healthy and its glucagon (and thus gluconeogenesis) inihibiting effects in diabetic individual (Abdula 2004 & 2008; Jeppesen. 2007), have already been reproduced in human trials, I would say that it is more than likely that we will see similar effects in humans, as well, once the correct dosing has been established

Note: especially if you use those combination products of stevia + sugar alcohol you are very unlikely to get sufficient amounts of stevia to elicit those restorative effects; this does not mean that this is a better alternative than aspartame or cyclamate, but in those tiny amounts stevia is a sweetener, not a substance with almost drug-like effects.

Table 1: What's in stevia leaves?
(based on Yadav. 2012)

The latter is by the way all the more likely in view of the fact that Maryam Mohammadi-Sichani and her colleagues from the Falavarjan Branch-Islamic Azad University and the Esfahan University of Medical Sciences in Iran found that stevia extracts will also kill S. mutans, a common bacteria in your mouth that has its share in the development of dental caries and shows, irrespective of generally lower caries rates in type I diabetics, a hitherto not fully explained correlation with (poorly controlled) type I diabetes (Siudikiene. 2006).

Your gut starts in your mouth: The stevia - bacteria connection

These observations stand in line with previous results, of a whole host of peer-reviewed studies Yadav & Guleria summarize in a 2012 review that's about to be published in the November edition of Critical Revision of Food Science, as follows :

Image 2 (20th Century Fox): You better feed your gut bacteria right, otherwise they will disbehave just like the Alien in Ellen Ripley in Alien 3  - read more about the "Gut Type Diet" and how what you eat influences the bacterial composition of your gut on the SuppVersity

"[...] Different extracts showed differential inhibitory activity against various microbes. This experimentation confirmed the antibacterial as well as antifungal potential of Stevia leaf extract and documented that Stevia might be a source of new non-antibiotic antibacterial and antifungal agent. Its antifungal activity was estimated to be higher than the standard fungicide usually used against plant pathogens. Such extraordinary antimicrobial activity of Stevia has presented it as a potent non-antibiotic pharmaceutical and an efficient food preservative. Stevioside alone has been observed to significantly reduce the amount of inflammation mediators and activate cytotoxic cells of the host. These activities suggested that stevioside might play a synergistic role with the innate immunity of the host. Thus stevioside is antibacterial, antifungal, anti-inflammatory, anti-tumorous, and safe for use. While at the same time rebaudioside A has been reported to be clinically insignificant." (Yadav. 2012; my emphases)

In other words, stevia could exert part of it's beneficial effects via the immune-modulatory effects it exerts due to it's impact on the human gut microbiome, the contribution of which to the etiology of both diet-induced type II, but also auto-immune type I diabetes is getting more and more attention among researchers, as of late:

"[...] the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. These data also suggest bacterial markers for the early diagnosis of T1D. In addition, bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children." (Giongo. 2011; my emphases)

And even if the whole "bacteria theory" of autoimmune disease and inflammation turns out to be yet another sidetrack - you will always have the

• beneficial effects on skeletal muscle insulin sensitivity and glucose uptake that has been established by Lailerd et al. in insulin sensitive and resistant mice and the 
• hopefully physiologically relevant increase in satellite cell activity, Bunprajun et al. observed earlier this year in response to lower NF kappa-beta activity (=modulation of inflammation) in an in-vitro model (Lailerd. 2004; Bunprajun. 2012) 

as additional* arguments to satisfy your sweet tooth with stevia instead of sugar or artificial alternatives (*in addition to being able to avoid the "alternatives").

And as long as you keep an eye on the overall amount of food you consume, instead of simply stuffing yourself until you feel like there was no tomorrow, the previously discussed effects any sweetener - natural, artificial, or whatever else the future may hold - could have on your ability to sense the energy density of your foods should not be all too much of a problem problem (cf. "Sweeter Than Your Tongue Allows").

References:

• Abudula R, Jeppesen PB, Rolfsen SE, Xiao J, Hermansen K. Rebaudioside A potently stimulates insulin secretion from isolated mouse islets: studies on the dose-, glucose-, and calcium-dependency. Metabolism. 2004 Oct;53(10):1378-81.
• Abudula R, Matchkov VV, Jeppesen PB, Nilsson H, Aalkjaer C, Hermansen K. Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K-channels. Diabetes Obes Metab. 2008 Nov;10(11):1074-85. Epub 2008 Apr 22.
• Das, K., R. Dang, L. Hegde and A.S. Tripathi. Assessment of heavy metals in dried stevia leaves by Atomic Absorption Spectrophotometer grown under various soil conditions. Middle–East J. Sci. Res. 2011; 8: 107-113.
• Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyöty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011 Jan;5(1):82-91.
• Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism. 2004 Jan;53(1):73-6.
• Jeppesen PB, Dyrskog SE, Agger A, Gregersen S, Colombo M, Xiao J, Hermansen K. Can stevioside in combination with a soy-based dietary supplement be a new useful treatment of type 2 diabetes? An in vivo study in the diabetic goto-kakizaki rat. Rev Diabet Stud. 2006 Winter;3(4):189-99. Epub 2007 Feb 10.
• Sharma R, Yadav R, Manivannan E. Study of effect of Stevia rebaudiana bertoni on oxidative stress in type-2 diabetic rat models Biomedicine & Aging Pathology. 2012 August 28.
• Siudikiene J, Machiulskiene V, Nyvad B, Tenovuo J, Nedzelskiene I. Dental caries and salivary status in children with type 1 diabetes mellitus, related to the metabolic control of the disease. Eur J Oral Sci. 2006 Feb;114(1):8-14.
• Yadav SK, Guleria P. Steviol Glycosides from Stevia: Biosynthesis Pathway Review and their Application in Foods and Medicine. Crit Rev Food Sci Nutr. 2012 Nov;52(11):988-98. 

30 Min of Exercise Can Avoid Costly & Unhealthy Gestational Diabetes. Carbohydrate Oxydation Determines Appetite After Workouts. Using a Measuring Tape to Judge Visceral Fat Mass. Update: Vitamin D, Age & Obesity.

85 sessions (general fitness class, three times/week, 55-60 min/session from weeks 8-10 to weeks 38-39 of pregnancy are nothing but healthy for mother + child (Barakat. 2013)

Obese mothers with gestational diabetes are more than just a financial burden. That's what the SuppVersity Figures of the Week clearly indicate.

According to a recently published paper from the National University of Ireland Galway woman who develop gestational diabetes during pregnancy (mostly due to pre-existing extra fat-pounds; not BMI), produce 34% higher health-care costs (Gillespie. 2013). Just as the 75% increase in the necessity to have the kids being delivered by cesarean section, this would still be tolerable, though, if their poor offspring did not also have a increased risk of being born with pathological ventricular hypertrophy (Ullmo. 2007) and a 214% higher likelihood of having to be admitted to the neonatal unit, which, in turn, is associated with "increased and/or aberrant adiposity, in addition to postnatal growth retardation" (Gianni. 2012).

Another good reason to (a) get healthy (and contrary to what the soothing news in the mainstream media will tell you this involves having normal body fat levels), before you even think of bringing a baby into this world and (b) not dropping your exercise regimen all-together, when you're pregnant:

 "A supervised program of moderate exercise performed throughout pregnancy is not a risk of preterm delivery for heal thy pregnant women." (Barakat. 2013) 

This, by the way, works not only in type II, but also type I diabetic mothers, whose chance of developing gestational diabetes and/or even more hazardous extreme spikes and troughs in blood glucose can be reduced from 19% to ZERO with only 30 min of light exercise per day (a self-paced walk in the park is enough!) and making the right food choices (Kumareswaran. 2013).

• Related D-News from Japan: Vitamin D deficiency in Japan comes with current smoking, being female, lack of regular walking and low dietary vitamin D intake, study shows (Yoshimura. 2013).
  

  Overall, 81.3% of the subjects in the study from the University of Tokyo were vitamin D insufficient - only 1.2%, though, had a full-blown deficiency, defined as 25OHD levels below 10 ng/ml.
  Being fat is a critical determinant of baseline vitamin D levels and the response to vitamin D supplement in older Irish adults (Forsythe. 2013).

  "In older adults, vitamin D status was inversely associated with BMI (kg/m2), WC (cm), FM (kg and %), FMI (kg/m2) and FM:FFM (%) at baseline (r − 0·33, − 0·36, − 0·33, − 0·30, − 0·33 and − 0·27, respectively, all P values < 0·01). BMI in older adults was also negatively associated with the change in 25(OH)D following supplementation (β − 1·27, CI − 2·37, − 0·16, P = 0·026)."

  What's surprising, though, is the fact that this correlation of which I have previously argued that is is probably based on the pro- and anti-inflammatory effects of obesity and vitamin D and initiated by being fat, not vitamin D deficient, was not present in the younger study participants.
  
  Just as a review I mentioned only a couple of days ago said: There is still much to learn about vitamin D - in that case D2 & D3 - and how their enzymatic hydroxylation influences both our baseline levels as well as their metabolic downstream effects (read more)

• Exercise does not make you hungry, per se, but the more carbs you burn during your workout the hungrier you're gonna be afterwards (Hopkins. 2013) That's the main finding of a recent study from the Leeds Trinity University in the UK.
  
  

  

  There comes a time, when getting fat and sick is no longer only about making the "wrong" food choices or a non-warranted urge to eat. A time, when neither the apple nor granny's pie will satisfy your hunger, and your cells will be starving within a nutritious cocktail of partially oxidized fatty acids and sticky glucose molecules... yet still, or I should say, exactly for that reason simply "cutting calories" won't solve the problem. Learn more about how this state is creeping up on the obesity generation (read more)

  According to the data the researchers gathered in the course of a bout of cycling individually tailored to expend 400 kcal (EX) or a time-matched no exercise control condition in a randomized, counter-balanced order,
  

  "[...] there was a marked individual variability in compensatory EI. The difference in EI between EX and the control condition ranged from -234.3 to 278.5 kcal. Carbohydrate oxidation during exercise was positively associated with postexercise EI, accounting for 37% of the variance in EI (r=0.57; p=0.02)" (Hopkins. 2013)

  That's particularly interesting, because the average total energy intake did not differ significantly between the exercise and the control condition (666.0±203.9 vs 664.6±174.4 kcal, respectively) in the overweight and obese women with a mean BMI of 29.6±4.0 kg/m².
  
  These observations provide further evidence of the detrimental effects of metabolic inflexibility, a classic characteristic of developing or full-blown metabolic syndrome and a state in which your body is heavily (in the worse cases almost exclusively) reliant on glucose as a substrate - a paradox, in view of the fact that thee aberrant insulin resistance of obese individuals has their cells starve in a state of glucose abundance (learn more)

• Toss your scale and use a measuring tape! Nothing predicts metabolic risk and high risk visceral fat as adequately as the circumference of your midsection (Grundy. 2013)
  
  As a SuppVersity reader you should actually have banned your scale into the depth of your "things I will never need again (!)"-cupboard, once you achieved a normal body weight (on a side note: I don't have a functional scale). From the many questions I receive on a daily basis, I do yet know that some of you are either hesitant to do that or fill inclined to get it back out from time to time to ruin their days and results by stepping on the scale at least thrice a week. If that's you, I suggest you take a peak at the results of a recent study from the Clinical Nutrition and Center for Human Nutrition and the Division of Cardiology of the University of Texas Southwestern Medical Center in Dallas.
  
  To find out whether or not a simple measuring tape by the means of which you would assess the circumference of your waist (WC) would be an adequate measure of total abdominal fat (TAF), abdominal subcutaneous fat (ASF) and intraperitoneal fat (IPF) Scott M. Grundy and his colleagues correlated the measuring tape data with results they had obtained from magnetic resonance imaging (MRI) and found an excellent correlation between WC and total abdominal fat (R² = 0.81 − 0.88) "with progressively lower correlations with ASF (0.65–0.82) and IPF (0.29–0.85)" (Grundy. 2013)
  

  

  Figure 1: Median intra-abdominal fat (median in kg), waist circumferences and corresponding intraperitoneal to total abdominal fat rario (IP/ABS x10) for quintile 1-5 of total abdominal fat in men (left) and women (Gruny. 2013)

  As hinted at in the arrow in figure 1 the accuracy of the waist circumference as a means to quantify the body fat levels and metabolic risk does not only depend on gender, but also on ethnicity, with African American men and women having lower median IPF masses than Whites and Hispanics, in general, but high(er) greater amounts of subcutaneous. In view of the fact that unlike IPF, ASF correlated only with HOMA2-IR, whereas elevated IPF values were also reliable predictor of high triglyceride levels, as well - African Americans may be at a slightly, but probably not significantly lower risk of developing heart disease (high triglycerides are a neat predictor here) than Whites and Hispanics of whom the latter tend to carry the most vicious visceral fat per cm on their waists.

Believe it or not, but that's it for today! I know that was fast and therefore I'll provide you with a couple of additional facebook news, you may be interested in.

• 

  The fact that simply dropping the weight and lying around for weeks could lead to fat gains is actually not that surprising right? So what can be done to make constant progress without overtaxing the system? One of the answers certainly is P-E-R-I-O-D-I-Z-A-T-I-O-N and the Step By Step Guide to Your Own Workout Routine is the series, where you can learn about planning your training schedule in the long and short run to maximize your results and accommodate it to your personal goals (read more)

  Is giving up physical culture worse for your health than being a sedentary slob in the first place Rodent study suggests there is propensity for increases in visceral fat gain during 4-week detraining that surpasses in previously trained rats that of the sedentary controlled (read more)
• Fooled again 2.0: By one way or another Subway bamboozles customers to believe their junkfood was less junky than that of the competition. According to a recent Harvard study, adolescents dining at Subway underestimate the caloric value of their nutrient deficient junk food by more than 500kcal! That's... (read more)
• The "starve yourself to live longer"-bubble is bursting! Now scientists realize that even in yeast, what you eat is more important than how much you eat and that the simple addition of a pH buffer can go a long way (read more)
   
• SuppVersity Suggested Read: Prolotheraphy? Can you actually HEAL those chronically painful tendons, ligaments and cartilage without having to resort to a butcher's... ah, I mean a surgeon's knife? My buddy Sean Casey just posted part II of his scientifically grounded answer (read more).

Now that you're through with these as well, all that's left to be said is: "Have a nice weekend, everyone, and don't forget that the SuppVersity is open on Sundays, as well!"

References:

• Barakat R, Pelaez M, Montejo R, Refoyo I, Coteron J. Exercise Throughout Pregnancy Does Not Cause Preterm Delivery. A Randomized, Controlled Trial. J Phys Act Health. 2013 May 10.
• Forsythe LK, Livingstone MB, Barnes MS, Horigan G, McSorley EM, Bonham MP, Magee PJ, Hill TR, Lucey AJ, Cashman KD, Kiely M, Strain JJ, Wallace JM. Effect of adiposity on vitamin D status and the 25-hydroxycholecalciferol response to supplementation in healthy young and older Irish adults. Br J Nutr. 2012 Jan;107(1):126-34. 
• Giannì ML, Roggero P, Piemontese P, Orsi A, Amato O, Taroni F, Liotto N, Morlacchi L, Mosca F. Body composition in newborn infants: 5-year experience in an Italian neonatal intensive care unit. Early Hum Dev. 2012 Mar;88 Suppl 1:S13-7.
• Gillespie P, Cullinan J, O'Neill C, Dunne F; ATLANTIC DIP Collaborators. Modeling the independent effects of gestational diabetes mellitus on maternity care and costs. Diabetes Care. 2013 May;36(5):1111-6. 
• Kumareswaran K, Elleri D, Allen JM, Caldwell K, Westgate K, Brage S, Raymond-Barker P, Nodale M, Wilinska ME, Amiel SA, Hovorka R, Murphy HR. Physical Activity Energy Expenditure and Glucose Control in Pregnant Women With Type 1 Diabetes: Is 30 minutes of daily exercise enough? Diabetes Care. 2013 May;36(5):1095-101. 
• Ullmo S, Vial Y, Di Bernardo S, Roth-Kleiner M, Mivelaz Y, Sekarski N, Ruiz J, Meijboom EJ. Pathologic ventricular hypertrophy in the offspring of diabetic mothers: a retrospective study. Eur Heart J. 2007 Jun;28(11):1319-25.
• Yoshimura N, Muraki S, Oka H, Morita M, Yamada H, Tanaka S, Kawaguchi H, Nakamura K, Akune T. Profiles of vitamin D insufficiency and deficiency in Japanese men and women: association with biological, environmental, and nutritional factors and coexisting disorders: the ROAD study. Osteoporos Int. 2013 May 15.

Vitamins B1, B2, B5 & B6 & Glucose Management | Part VII of the "There is More To Glucose Control Than Low Carb"- Series. Any Real Benefit From Supplementing With "Bs"

Funny or obscene? A woman w/ low vitamin B and thus fortified cornflakes is among the "top images" Google will show you, when you search for B-vits

There is an often overlooked reason I am addressing thiamin (B1), riboflavin (B2), panthotenic acid (B5) and pyridoxine (B6) in one installment of the "There is More to Glucose Control Than Carbohydrates"-Series (read previous installments): They are all necessary to store glycogen in the liver (Supplee. 1942).

In general, a whole foods diet, as recommended in previous SuppVersity articles will easily cover the B-vitamin needs of the average sedentary and physically active individual - in spite of minimally increased requirements for B2 & B6, in particular (Manore. 2000; Woolf. 2008).

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

As a SuppVersity reader you do yet know that "adequate" and optimal intakes can differ significantly and the fact that the provision of additional B-vitamins does not have ergogenic effects does not exclude the possibility that it may have beneficial effects on blood glucose management.

The initially mentioned inability to convert glucose to glycogen and to store the latter in the liver, for example, would already set you up to increases in blood glucose levels. The latter will in turn increase the urinary loos of the water-soluble vitamins, so that a deficiency in one of the initially named B-vitamins could trigger a whole "pro-diabetic" cascade that leaves the by then (pre-)diabetic individual deficient even in those of the B-vitamins of which he or she is actually getting enough from his or her diet (+ supplements).

Annual spending Alzheimer patients >65y in the US from 2010 to 2050 (projection, in billion U.S. dollars;  Alzheimer's Association. 2010)

This article is exclusively about the beneficial effects of b-vitamins on glucose control: The conclusions I draw based on the evidence presented in this article do not affect potential cognitive benefits from "optimal" (=within the RDA) intakes of B-vitamins (in particularly folate, and B-12, which are not part of this overview, anyway) in the young (Herbison. 2012) and old , where they are furthermore "confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline" (Douaud. 2013).

Conclusive evidence for anti-diabetic or insulin-sensitizing effects of B-vitamin supplements is yet still scarce. Even the notion that (pre-)diabetics suffer from low levels of the said B-vitamins is still controversial. This does not mean, though, that there were no promising study results I could report. For thiamine, for example, ...

• 

  Figure 1: Effects of lipophilic thiamine on HbA1c (top) and insulin requirements (bottom) of type I diabetics (Valerio. 1999(

  Valerio et al. report that the provision of a lipophilic form of thiamine (benzoyloxymethyl-thiamin) at 50mg/day lead to improvements in HbA1c and reduced insulin requirements in children with type I diabetes (Valerio. 1999) - the difference between the active and the placebo arm of the study did yet not reach statistical significance
• Obrenovich et al. report in a 2003 that thiamine, or rather benfothiamine bocks the oxidative damage due to the presence of excessive amounts of glucose in the blood of a rodent model of diabetes - their results have been replicated in human studies by Stirban et al. an other researchers several times over the past decade (Stirban. 2006)

Corresponding evidence for riboflavin is hard to find. While there are studies that suggest the presence of reduced levels of this b-vitamin in both type I and type II diabetics, direct beneficial effects of vitamin B2 supplementation on glucose management have not been reported.

A very similar picture, i.e. reduced levels in type II diabetics, but no reports of direct metabolic benefits from the provision of supplemental vitamin B5 from randomized controlled human trials, emerges if you do a database search for panthotenic acid.

Figure 1: 2h glucose and insulin response to oral glucose tolerance test before (white) and after 25 days of B5 depletion (red), as well as during B5 refeed (violet) in a healthy male subjects (Bean. 1995)

The results of a study from the mid 1950s, when scientists still put healthy individuals on nutritionally deficient diets still indicate. After 25 days without significant amounts of panthotenic acid in the diet, the subjects' insulin sensitivity was notably compromised (Figure 1, red) and was not normalized within only 10 days on a diet with 133x the normal amount of panthotenic acid (Figure 1, violet).

Mind the vitamin <> vitamin interactions: Even if there is no reason for high dose pantothenic acid supplementation to inhibit the cellular uptake of glucose directly, it's well possible that it messes with glucose metabolism via interactions with other water solube vitamins like vitamin B6 aka pyridoxin, the excretion of which is increasing, whenever the intake of panthothenic acid exceeds an (in humans undetermined) sane threshold.

In fact, the extreme elevation of the insulin levels in the "reload phase" would rather suggest that extreme amount of vitamin B5 will compromise, not improve your insulin sensitivity - contrary to edema, severe fatigue, joint pains, reduced protein metabolism, reduced phosphorus, raised VLDL triglycerides, calcification (from calcium pantothenate), dehydration, gastrointestinal symptoms, and depression, a decreased insulin sensitivity is yet not on the "official list of side effects"* of high panthotenic acid intakes (*by "official" I refer to the lists everyone copies ad pastes from the major health information outlets on the Internet).

And what about B6? It's in all my supplements, so it must be good!

If I had to write the bottom line to today's installment of the "There is More to Glucose Control Than Carbohydrates" series now, it would probably be very short and certainly very disappointing for the various supplement junkies out there. Luckily (?) there is still one of the B-vitamins missing: Pyridoxine or vitamin B6 - and you should expect the only B-vitamin that can produce severe toxic effects when it is consumed in very high amounts chronically (peripheral nerve damage) should be able to bring about at least minimal increases in insulin sensitivity / cellular glucose uptake, as well, right?

Well, unfortunately, that's not the case. In 1980, already, a group of scientists from the Gandhi Medical College Hospital in India were able to show that the provision of 40mg of pyrodixine per day had "did not bring about any significant alterations in either the oral glucose tolerance or the insulin response to glucose" in thirteen adult maturity-onset diabetics - and that in spite of the fact that 7 of them were actually vitamin B6 deficient!

Mind the "hidden" B-sources: If you are still concerned that you may not be getting your Bs in, you are probably an OTC supplement junkie. In that case I suggest you briefly take a look at the pre-workout, post- workout and whatever other products in your stack... what? Oh, they all contain 10x the RDA and more of these B-vitamins - that's surprising, right?

A major disappointment? Although this article focused exclusively on the benefits of the water-soluble B-vitamins on glucose control, the results are still paradigmatic for the overall "potency" of vitamin-B-supplements. They are all the rage, but the benefits are overblown, in many cases simply non-existent.

If we discard the well established beneficial effects of benfothiamine on the side-effects of elevated blood glucose levels, and the highly disputed benefits of pyridoxine in diabetic peripheral neuropathies (alleviation of sympthoms, no change in nerve damage; Bernstein. 1988 & 1990), there is actually no reason to even consider taking extra amounts of any or all of these vitamins if you are (a) no diabetic and (b) no junk food eater - and let's be honest, if either (a) or (b) applies you have got more important issues to deal with than potentially suboptimal B-vitamin intakes and their effects on glucose tolerance.

Reference:

• Bean, William B., et al. "Pantothenic acid deficiency induced in human subjects." Journal of Clinical Investigation 34.7 Pt 1 (1955): 1073. 
• Bernstein, A. L., and C. S. Lobitz. "A clinical and electrophysiologic study of the treatment of painful diabetic neuropathies with pyridoxine." Current topics in nutrition and disease (USA) (1988).
• Bernstein, Allan L. "Vitamin B6 in clinical neurology." Annals of the New York Academy of Sciences 585.1 (1990): 250-260.
• Herbison, Carly E., et al. "Low intake of B-vitamins is associated with poor adolescent mental health and behaviour." Preventive medicine 55.6 (2012): 634-638.
• Manore, Melinda M. "Effect of physical activity on thiamine, riboflavin, and vitamin B-6 requirements." The American journal of clinical nutrition 72.2 (2000): 598s-606s.
• Supplee, G. C., R. C. Bender, and Z. M. Hanford. "Interrelated vitamin requirements. The influence of thiamin, riboflavin, pantothenic acid and vitamin B6 on liver glycogen reserves." Journal of the American Pharmaceutical Association 31.7 (1942): 194-198.
• Valerio, G., et al. "Lipophilic thiamine treatment in long-standing insulin-dependent diabetes mellitus." Acta diabetologica 36.1-2 (1999): 73-76.