Classic Beats Super Slow; Single 198 Second Sprint More Time Efficient Than Work-Matched HIIT; Exercise Better Than THC; Metformin + Cardio + Lifting = Anti-Obesity Triplet; Self-Efficiacy & Training Adherence - Plus: More!

This is just a random selection of the unlimited movement patterns your body has been designed to execute - don't make the mistake and rely on only one of them!

The amount of really interesting, let alone revolutionary new studies on the effects of different exercise modalities is not exactly high, to say the least. I am not quite sure, what the reasons are, but as I have stated before, part of it certainly is that you cannot monetize on the results by producing patentable drugs based on your findings and will thus have a hard time to find sponsors / get funding. It is therefore no wonder that many published papers are spin-offs of small scale trials that have been conducted as part of dissertations. Others simply use rodent models, which may provide relatively reliable data, when it comes to the effects of running on a treadmill, but are not exactly what I would want to see, when it comes to weight lifting or any other of the myriad complex movement patterns our bodies can, but these days way too often don't do.

I have nevertheless been able to compile another potpourri of studies of which I would hope that one or the other will enlighten or at least entertain you. That being said, let's get started with this weeks installment of the Exercise Science Special of "On Short Notice", here at the SuppVersity...

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HIT it short, hit it hard, hit the glucose and be smart! Yo, this awesome rhyme would be my advice to the very busy chubby manager-types with compromised insulin sensitivity out there and it's based on the results of a very recent study by scientists from the Institute of Cardiovascular and Medical Sciences at the College of Medical, Veterinary and Life Sciences of the University of Glasgow in the UK (Whyte. 2012)

Figure 1: Power, workload (top) and metabolic effects of SIT and ES regimen (vs. control; bottom)

When Laura J. Whyte and her colleagues compared the effects of the single bout of very high-intensity exercise (SIT: 4x 30-s maximal sprints w/ 4.5min recovery between each) to a single maximal extended sprint (ES) matched with SIT for work done, they found that the immediate advantage of higher insulin sensitivity (measured via oral glucose tolerance test) in the work-matched continuous sprint the shorter duration 190s (TOTAL!) as well as almost identical...

• decreases is RER and carbohydrate oxitation, and
• increases in fatty acid oxidation

on the day after the exercise bout, in the presence of statistically significant reductions in insulin sensitivity only after the ES trial.

In other words: A single all out sprint on a braked cycle ergometer (as fast as you can; with obviously decreasing power in the course o the sprint) elicits greater metabolic effects within a 85% shorter timespan (198s vs. 1360s!), than work-matched classic HIIT training, with allegedly very long periods of active recovery.

That being said, I strongly caution against taking the results of this study as an incentive to perform the classic "go as fast as you can, for as long as you can" HIT sessions on exercise bikes, treadmills or ellipticals - those SUCK! *full stop* Be smart and either perform that one 3min sprint (if you really have no more time), or modify your HIIT training to incorporate longer high intensity phases (45-90s) at a work to active recovery ratio of 1:3 - 1:2, so that a resulting workout could look like that 4x 60s sprints, interspersed by 120s of active recovery. I would bet money that this protocol outperforms a work-matched continuous sprint in terms of its immediate and long-term metabolic effects.

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Opioid-like effects of exercise depend on intensity I guess you will be familiar with the term "runner's high"? Now, while the latter is usually ascribed to the exercise induced release of serotonin, the improved affect, the sense of well-being, the anxiety lowering and calming effects of exercise are probably mediated by the release of endocannaboids, of which scientists from the University of Arizona, the University of Texas Health Science Center and the Eckert College in St. Petersburg, Florida, have recently shown that the levels of these endogenous THC-like compounds depends on the intensity of the workout (Raichlen. 2012).

Liar, liar, THC junkie on fire ;-) You don't need to smoke weed before a workout if you get the intensity right! But could exercise also help people who recover from major depression to battle their tendency to obsess with negative thoughts and feelings?

At least in the 10 healthy regular runners who participated in the study, the results of which have been published in the Journal of Applied Physiology the endocannaboid exercise induced increase in circulating anandamide was most pronounced (~2x), when the subjects exercised at ~72% of their maximal heart rate (the workout consisted of 30min of treadmill walking, jogging, running at 45, 72, 83, and 92% of their maximal heart rate). Moreover, the post hoc analysis of the blood samples that had been immediately before and after the workout revealed that exercising at both the lowest and highest intensities had the exact opposite effect, although the reductions in serum anandamide were - when considered in isolation - were not statistically significant.

In conjunction with the results of another recent study that has been conducted at the Stanford University, it becomes evident that these results could actually be more than just "scientific masturbation", so to say. The Stanford researchers compared the reactions of 41 female patients who had recovered from major depressive disorder (MDD) and those of 40 healthy control, both of whom had been randomly assigned to either exercise for 15 minutes or quiet rest, to two sad mood inductions (once before and once after exercise or rest) and found that

"[while r]ecovered depressed participants who had not exercised exhibited higher NA [neagtive affect] after the second sad mood induction [...], both recovered depressed participants who had engaged in acute exercise and healthy control participants showed no increase in NA in response to the repeated sad mood induction." (Hogan .2012)

A reaction that goes against the so-called sensitization effect, which describes the tendency of depressed people (or people with a propensity to develop depression) to react with an increased level of negative effect to a repeated negative stimulus (Eisenstein. 2001) and would thus predict an increase in negative affect in response to the second stimulus as it was observed in the non-exercise group (figure 2, red box).

Figure 2: Negative and positive affect after 1st and second sad mood induction (left) and before and after exercise (right), respectively, in 41 female patients who had recovered from major depressive disorder (data from Hogan. 2012)

Moreover, the 15 minutes of exercise at an intensity the participant felt comfortable with led to an increase in positive affect participants in the exercise groups after the exercise bout, but failed to produce the same beneficial effect on the positive affect in the subsequent double-exposure to the filmic sad mood stimuli:

"However, in contrast to our hypothesis, we did not find any interaction between exercise condition and diagnostic group in level of reported PA following the repeated sad mood inductions that would be consistent with the notion of sensitization or habituation." (Hogan. 2012)

And who knows, if the exercise intensity had been higher, so that there had been more anandamide and other endocannaboids floating around in the brains of the study participants, this could even have changed the positive affect trajectory from the first to the second filmic sad mood induction? "Yo, that's so sad... hahaha" ;-)

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Image 1: Otsuka Long-Evans Tokushima fatty rats (OLETF, right) have a  genetic disposition to develop type II diabetes.

When metformin is good for the obese (pre-)diabetic and exercise is good, as well, metformin + exercise cannot be bad, right? At least in OLETF rats, one of the common rodent models of the metabolic syndrome, this assumption appears to apply (Jenkins. 2012).

According to the recently published paper by Nathan T. Jenkins and his colleagues, metformin and exercise do in fact work synergistically - at least as far as the obesity induced inflammation is concerned. While metformin decreased the pro-inflammatory overexpression of leptin, the rodents that have been exposed to an endurance type exercise regimen exhibited higher levels of the anti-inflammatory cytokine IL-10, which limit and ultimately terminate inflammatory responses (Moore. 2001).

Not just in view of the fact that IL-10 has also been implicated in the prevention and even treatment of auto-immune diseases, such as lupus erythematosus and multiple sclerosis (Beebe. 2002), I would always choose exercise over metformin - this is all the more true, if you are not morbidly obese in the first place!

And if you want to go even one step further, you simply add couple of interval sprints to the equation as those have been shown - in the same rodent model, by the way - to elicit greater improvements in HbA1c, the long-term marker of glucose management that "classic" steady state endurance exercise (Martin. 2012). Since the latter were mediated via differential microvascular changes than those Martin et al. observed in endurance trained OLETF rats, it is furthermore almost certain that they will add up. Probably not 1+1, but 1.5 and even 1.1 would still be better than 1.0, wouldn't it?

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The lack of the feeling of  self-efficacy is one of the best predictors of not sticking to a workout routine. And you know what? Oftentimes it's not your your, Joe or Jane who is to blame, but simply their cookie-cutter trainer or unqualified cousin who's dragging them to the gym. Now, think about that... could it be that you are a cousin / trainer like that!? No way, right?

A feeling of accomplishment is one of the main determinants of exercise compliance Have you ever wanted why you really enjoy going to the gym, while your obese cousin will only drag his ass over there if you kick him into the latter? Well, according to the latest study from the Johns Hopkins University School of Nursing and Division of Cardiology at the The Johns Hopkins University School of Medicine in Baltimore, Maryland, it may in fact be you and not Joe or whatever his name is, who is to blame. Probably you are just having him copy what you do, with either way too much weight, or so little weigh that he does not just feel bad about it, but cannot make real progress either (Nam. 2012).

The scientists call that which Joe is lacking a feeling of "self-effiacy", when he is going to the gym training next to his 75lbs lighter cousin, lifting sissy weights and looking like a fat balloon.

No wonder he is falling off the wagon! Specifically, if you also take into consideration that in addition to the missing feeling of accomplishment, which increases his chance of non-compliancy by 19%, Joe also exhibits most of the other features Nam et al. have found to increase the chance of dropping out, specifically,

• low fitness - 26% increased chance of dropout and
• higher insulin resistance - 17% increased chance of dropout,

in the course of their experiment with 140 overweight, sedentary individuals with type II diabetes, who were randomly allocated to a 6-month, 3 times per week exercise intervention or a non-exercise control. And while bodyfatness, i.e. a higher total and subcutaneous abdominal fat percentage appeared to be indicators of higher compliance, when the scientists just looked at the raw data, these positive effects vanished, when they plied a multiple logical regression analysis.

So what's the take home message, here? Cousin or not, people won't do well on cookie cutter plans that won't allow them to make, see and feel progress.

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Isn't it astonishing how versatile and important these stem cells from the bone marrow are (image NIH. 2001)

1h of exercise thrice a week increases hematopoietic stem cell (HSC) count in the bone marrow With the almost magic effects of stem cell therapy being on everybody's lips, these days. You will probably be intrigued to hear that researcher from the McMaster University have recently established that a very reasonable amount of 3x 1h of exercise per week increased the quantity of hematopoietic stem cells in the bone marrow of exercised mice by +20% compared to their sedentary peers (de Lisio).

With it's likewise statistically significant effect on the proportion of whole BM cells in G(2)/M phase of cell cycle (p<0.05 and an increase in the number of spleen colonies (+48%, p<0.05) in those "model patients" who received transplants from the exercised compared to transplants from sedentary mice, it is thus likely that people who exercise regularly will benefit from both the quantitative increase, as as well as the qualitative improvements these multipotent stem cells, which  give rise to all the blood cell types from the myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells), undergo in response to a moderate amount of exercise.

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Finally acknowledged: "[C]ombination exercise g[ives] greater benefits for weight loss, fat loss and cardio-respiratory fitness than aerobic and resistance training modalities", alone! And this is only the first part of the conclusion of a recently published paper by Suleen S Ho, Satvinder S Dhaliwal, Andrew P Hills and Sebely Pal, who explicitly suggest that

"Therefore, combination exercise training should be recommended for overweight and obese adults in National Physical Activity Guideline" (Ho. 2012)

How the scientists came to that conclusion? Well they could simply have read the SuppVersity news, but instead they conducted a 12-week trial, in the course of which 97 overweight or obese men (n = 16) and women (n = 81) (BMI >25 kg/m² or waist circumference >80 cm for women and 90 cm for men), aged 40 to 66 years, were randomly assigned to a either aerobic, resistance or combined training regimen (n=16 for each) or a sedentary control group (n=15). The results, spoke for themselves.

Figure 3: Changes in body fat (%; top) and VO2Max (bottom) in the course of the 12-week trial (based on Ho. 2012)

In the absence of statistically significant reduction in energy intake, or macronutient composition, the combination subjects in the combination group were the only ones to lose statistically significant amounts of

• body weight (-1.6kg),
• body fat (-1.9kg or 1% body fat), 
• android (=visceral) fat (-1.3kg),

had the most pronounced reduction in waist circumference (-2.6% vs. -2.5% in RT and -2.0 in AT) and were the only ones with statistically significant improvements in VO2Max, a marker of general cardiovascular fitness.

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Is there maybe more room in your training regimen for slow reps, than you may have thought? If you go by the statement "Slow speed-resistance training induced a greater adaptive response compared to training with a similar resistance at 'normal' speed" from a paper by Mark D. Schuenke and his colleagues from the University of New England, the Rocky Vista University, the College of Health Sciences and Profession and the Ohio-University that was published in the October Issue of the Journal of Applied Physiology (Schuenke. 2012), it would seem so.

If you do however take a closer look at the actual results you realize how important the adjoining qualificatory remark "However, training with a higher intensity at 'normal' speed resulted in the greatest overall muscle fiber response in each of the variables assessed" really is. After all, the "intensity" is per definitionem 20-45% higher in a classic strength training regimen compared to the often laughed at slow-speed resistance training (SS), which was - at least in the study at hand - defined as follows:

• SS: 6-10 reps, super-slow (10s) concentric (no typo!) and slow (4s) eccentric TUT, 40-60% of the individual 1-RM

Both the traditional strength training (TS) as well as the strength endurance regimen (TE) to which this protocol was compared used a TUT of 1-2s on the concentric and eccentric phase, but differed in terms of the weight and rep-numbers, which were

• TS: 6-10 reps at 80-85% 1-RM
• TE: 20-30 reps at 40-60% 1-RM

So, based on the qualificatory remark and a short glimpse on figure 4 you already know that the TS regimen yielded the best results during this 6-week resistance-training program that targeted the quadriceps femoris muscle group, in a total of 17 training sessions (only 2 in the first week), which were supervised to ensure that the 34 young, untrained female participants went to positive failure within the targeted repetition range on all three sets of the three exercises (leg press, squats, and knee extension) they performed after brief warm-up with ~2 min rest between sets and exercises.

Figure 4: Changes in body composition (left) and changes in muscle fiber cross-sectional area (all expressed relative to group baseline; data calculated based on Schuenke. 2012)

What's still missing though is the effect on overall body composition, where the super slow regimen did in fact produce almost identical results, while the "pump" workout ... ah, I mean the "strength endurance workout" sucked here just as it did as far as its effect on the increase in growth the number of hypertrophy-prone type II fibers is concerned.

So what's the take home message here? If you want some diversity, you can incorporate super slow sets into your regimen... but do you have to? At least based on the results of the study at hand, which was unfortunately conducted with untrained young women (who by the way love this alternative training styles) and is therefore not exactly representative for the average advanced trainee, the answer is "rather not, no!"

What neither the advanced nor the rookie who is striving to improve his or her body composition should do, however, is to train in the hilarious strength endurance range of 20-30 reps per set. If you want to build muscular endurance you either go out sprinting, beat the punching bag or do plyometrics.

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As I know you, you still want more, hah? Well, too much volume is not good for you and in case you cannot wait until next week, there will be some intriguing exercise news in the days to come, probably more on the SuppVersity Science Round-Up with Carl Lanore, on the Super Human Radio Network on Thursday, this week and obviously every day on the SuppVersity Facebook Wall @ www.facebook.com/SuppVersity - like it and always be the first to now!


References:

• Beebe AM, Cua DJ, de Waal Malefyt R. The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev. 2002 Aug-Oct;13(4-5):403-12. 
• Eisenstein, E. M., Eisenstein, D., & Smith, J. C. The evolutionary significance of habituation and sensitization across phylogeny: A behavioral homeostasis model. Integrative Physiological & Behavioral Science. 2001; 36, 251–265.
• Ho SS, Dhaliwal SS, Hills AP, Pal S. The effect of 12 weeks of aerobic, resistance or combination exercise training on cardiovascular risk factors in the overweight and obese in a randomized trial. BMC Public Health. 2012 Aug 28;12(1):704.
• Jenkins NT, Padilla J, Arce-Esquivel AA, Bayless DS, Martin JS, Leidy HJ, Booth FW, Rector RS, Laughlin MH. Effects of Endurance Exercise Training, Metformin, and their Combination on Adipose Tissue Leptin and IL-10 Secretion in OLETF Rats. J Appl Physiol. 2012 Sep 27. 
• de Lisio M, Parise G. Characterization of the Effects of Exercise Training on Hematopoietic Stem Cell Quantity and Function. J Appl Physiol. 2012 Sep 27.
• Martin JS, Padilla J, Jenkins NT, Crissey JM, Bender SB, Rector RS, Thyfault JP, Laughlin MH. Functional adaptations in the skeletal muscle microvasculature to endurance and interval sprint training in the type 2 diabetic OLETF rat. J Appl Physiol. 2012 Aug 23.
• Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.
• Nam S, Dobrosielski DA, Stewart KJ. Predictors of Exercise Intervention Dropout in Sedentary Individuals With Type 2 Diabetes. J Cardiopulm Rehabil Prev. 2012 Sep 24.
• National Institute of Health (NIH). Stem Cell Information Webpage. June 17, 2001. < https://stemcells.nih.gov/info/2001report/chapter4.asp > retrieved on Oct 01, 2012.
• Raichlen DA, Foster AD, Seillier A, Giuffrida A, Gerdeman GL. Exercise-induced endocannabinoid signaling is modulated by intensity. Eur J Appl Physiol. 2012 Sep 19.
• Whyte LJ, Ferguson C, Wilson J, Scott RA, Gill JM. Effects of single bout of very high-intensity exercise on metabolic health biomarkers in overweight/obese sedentary men. Metabolism. 2012 Sep 19.

Alpha Lipoic Acid, GABA, Taurine, Green Tea, Gooseberry & Fenugreek. Plus: Metformin the No.1 Drug? Supplements to Improve and Restore Insulin Sensitivity - Serving #1

Don't forget, those caps and pills are not worth a penny without you committing to the all the lifestyle changes I outlined in episode one of this series.

I am well aware that you had to wait for a full week for this 2nd part of the "Restore & Maintain Insulin Sensitivity" Series (read part I), so I am going to make no words about it and get straight to the annotated list of useful supplements.

Just a reminder for the lazy asses: Don't even think about starting any of the supplements on the list, if you have not already cut your carbs to a low, but not very low level, got rid of all plain sugar in your diet, started to work out frequently, get enough sleep, avoid stims and control (not totally eradicate) your linoleic acid (omega-6) intake.

Here we go, for serving #1

In order to give you at least some guidance on where you may want to start, I will classify the supplements in 4 very broad categories with

• [A] for supplements that are almost certainly useful,
• [B] for supplements that are potentially useful and definitely worth trying,
• [C] for supplements that are marginally useful and probably worth trying, and
• [D] for supplements that are simply bullocks and not even worth trying

Whenever I feel confident to do so, I will also suggest a concrete dosage - in some cases, such as GABA, I can however neither do the former, nor the latter, because there simply is too little quality research out there.

• Did you know that continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction in women with PCOS who have long been advised to stop metformin during pregnancy (cf. Nawaz. 2008)?
  Metformin [A]: Technically it is not a supplement, but let's be honest, who except for the FDA cares? Many supplements work as effectively as pharmacological drugs, but as far as real insulin sensitizers are concerned metformin still appears to have the edge on the rest of the pack (supplement or drug): It has an excellent safety profile (even in gestational diabetes, which has long been thought of being the one area of application, where metformin was not the first line intervention of choice; cf. Lautatzis. 2013). It works via a similar mechanisms as dieting and exercise does (→ AMPK; this is actually imho it's main advantage - an advantage it shares with lipoic acid btw.). And metformin has only recently been shown not to inhibit the benefits of exercise on glycaemic control or fitness (Boulé. 2013).
  
  Moreover, hundreds of studies support the preventive effects of metformin against the manifestation of tumors of pancreas, breast, colorectum, liver, endometrium and ovary. The prognosis of diabetic cancer patients on metformin therapy seems be better, than in diabetics without metformin treatment (Anděl. 2013).
  
  So, if you belong those people who have real issues and not just slightly elevated blood glucose levels, have your metformin prescription filled - it's unquestionable an [A] among the agents that can help you restore your insulin sensitivity [I don't have to tell you that this is not an agent you would use simply to stay insulin sensitive, right?].
  
  One thing you should keep in mind though, is that it may lower your B12 levels. While this could be a simply results of increased usage and more recent studies question previous reports according to which metformin radically depletes B12 levels have been questioned lately, it probably won't hurt to take 500-1,000mg of methylcobolamine alongside your metformin.
• Alpha lipoic acid (ALA) [A]: In a way lipoic acid, a naturally occuring organosulfur compound derived from octanoic acid, is a cousin of metformin. Unfortunately (for the future of alpha lipoic acid as an anti-diabetes agent and the diabetics who have ever since been treated with pro-obesogenic PPAR-agonists) the pharma industry realized that selling a natural and thus non-patentable anti-diabetes drug would not only generate a lower revenue, it would also hamper the sales of patentable and thus more profitable drugs.
  
  
  Don't take lipoic acid instead of working out. Why? Well, alpha lipoic acid has been shown to increase the arthesclerosis risk in a human trial by McNeilly et al. In the said study, 1g of alpha lipoic acid per day increased the cardiovascular disease risk, in 24 obese individuals with impaired glucose tolerance who participated in the experiment (McNeilly. 2012); the underlying mechanism was an increase in LDL oxidation that did albeit occur only in the "ALA only" but not the "ALA + exercise" group.
  Luckily, there are still more than enough animal and human studies (Jacob. 1999; Xiang. 2011; Porasuphatana. 2012) to support the beneficial effects lipoic acid will have on glucose management and hyperglycemic damage in (pre-)diabetics.
  
  In view of the fact that it could contribute to the development of heart disease precipitate hypoglycemic episodes (Khamaisi. 1990), has negative effects on appetite (which is the main mechanism by which it reduces weight gain in rodents) and appears to mess with lean mass gains - suggested reads ("You Could be Just as Lean, but More Muscular Without a Nutrient Repartitioner" (learn more); "Further Evidence Against Anti-Oxidant Supplementation: Vitamin E + Alpha Lipoic Acid Reduce Skeletal Muscle Mitochondrial Biogenesis" (read more) I would still not suggest you take high doses (>100-200mg) if you don't have problems with keeping your blood sugar levels in check.
  
  For those of you, who have established problems with managing their glucose levels, taking 2x250mg-600mg (with meals) would yet be a good point to start from (keep an eye on how it affects your glucose levels and adjust the dosage appropriately).
  
  With respect to the purported superiority of R-ALA vs. the regular (=racemic mixture) version of lipoic acid, I can only repeat that I am still waiting for someone to show me a study that would prove that R-ALA is more potent than regular the cheap racemic mixture that's been used in the vast majority of the currently available (mostly beneficial) studies.

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  Figure 1: GABA does effectively restore "almost" normal glucose levels in severly diabetic mice; the dosage is not mentioned in the FT or the supplemental material (Soltani. 2011)

  GABA [?]: No, the reason GABA (Gama-aminobutyric acid) is on the list is not that it will make you sleep better (although this may - for some(!) people, actually be the case). It's rather its direct protective and even restorative effect on pancreatic beta-cells (Soltani. 2011; Tian. 2013).
  
  Despite the fact that we have known about these effects for decades, up to now nobody seems to be interested to do or finance the research that would be necessary to make concrete and reliable dosage-recommendations. In fact, the evidence is still so scarce that we cannot even say: "Yes, GABA is definitely going to help" - if the prelminary evidence we have translates from the petri dish to the rodent cage and into the real world, it could however be the #1 agent on this list. Why? Well, this would basically mean that it could cure diabetes even when you have progressed from being insulin resistant to being a full-blown diabetic.
  
  The best evidence we have that this could in fact be the case does probably come from a 2011 study by Soltani, who have actually taken the important step from the petri dish to the rodent model and were able to show that  GABA restores β-cell mass and reverses diabetes in severely diabetic mice.
  
  
  Warning: Don't start out with 5g of GABA in one serving - esp. not on an empty stomach. This is not only going to give you parestesia (tingles), but could also have you gasp for air and have problems keeping on your feet, due to the profound actions on peripheral GABA receptors.
  Furthermore, human studies from the eighties have shown that 5g and 10g of GABA (consumed orally) exert direct insulinotropic effects (remember insulin resistance is not about too much insulin, but about the latter having no / too little effect on glucose uptake) and since oral GABA does not cross the blood-brain-barrier it's safe to be consumed by humans in relatively high doses (cf. Cavagnini. 1982). Still, as in the case of lipoic acid, GABA is not patentable and the stocks of the big players in the anti-diabetes drug business would certainly take a tumble, when someone actually proved that you could reverse diabetes by simply taking X grams of GABA everyday.
• Taurine [B]: You will remember that I mentioned Taurine only 2 days ago in the context of the anti-diabetic effects of whey protein (read more). You will probably also remember the numerous previous posts on the beneficial effects of taurine specifically for people with diabetes or pre-diabetes (learn more about taurine). I will therefore stick to a brief overview of the direct and indirect (protection against negative effects of high blood glucose) benefits taurine has to offer for people with insulin resistance and high glucose levels.

  • 

    Figure 2: The effects of taurine supplementation on glucose and insulin (top, left & right) 0, 6, and 12 weeks after beginning the taurine-supplemention in OLEFT rats (rodent model of diet induced diabesity), as well as the reaction to an insulin tolerance test and corresponding changes in insulin sensitivity (bottom, left & right; adapted from Kim. 2012).

    Taurine shows "independent of hypoglycemic effect in several animal model" (Ito. 2012)
  • It ameliorates both high glucose and lipid levels (Kim. 2012)
  • Taurine improves NO mediated blood glow in the corpus cavernosum (=battles erectile dysfunction) due to diabetes (Dalaklioglu. 2013)
  • Taurine exerts cardio-protective effects, partly via direct effects on the angiotensin II type2 receptor expression (Li. 2005)
  • It restores normal platelet aggregation in diabetics (Franconi. 1995)
  • Taurine protects the kidneys (Yao. 2009)
  • Taurine reduces mortality risk upon long-term administratio (rodent model; Franconi. 2004) 
  • It has a higher ability to reduce insulin resistance and stronger antioxidant properties than the diabetes drug glibenclamide (El Zahraa. 2012)
  • It protects the eye from diabetes induced damage (Hansen. 2001 Kim. 2007)
  • Taurine has protective effects against all components of the metablic syndrom (Hansen. 2001; Imae. 2012)
  • It increase the levels of conjugated tRNA, restore respiratory chain activity, and increase the synthesis of ATP at the expense of superoxide anion production (Schaffer. 2009)
  Beta alanine is the taurine antagonist #1: SuppVersity readers should know that (read more), but I guess I better repeat it: The "best" way to deplete taurine levels is the ingestion of copious amounts of beta alanine 24/7 (the side effects are similar to those of diabetes related taurine depletion, eg. Waterfield. 1993 → lowered protection against CCL induced liver damage). From a performance perspective there is as of now no evidence that you would need more than 2.5g of beta alanine per day, anyway. So why would you want to waste money and cellular taurine on additional beta alanine ;-)
  It should be mentioned thought that there are also studies which did not support the beneficial results reported above - they are not numerous, but may yield some insights into effective vs. uneffective dosage regimen.
  
  The 1.5g/day the overweight subjects with a predisposition for developing diabetes the subjects in a 2004 study by Brøns et al. received, may for example simply have been too little to exert any effects (Brøns. 2004). Based on the human equivalents of rodent studies, it appears most promising to distribute a daily taurine intake of 3g to max. 6g over your three main meals.
  
  Since taurine does also act as a gaba-ergic small molecule neurotransmitter (Albrecht. 2005), I would yet suggest you keep a close eye on (a) initial sedative effects and (b) longer term increases in anxiety - both of which have been reported in animal studies with allegedly higher and / or intracerebral administration of taurine.
  
  The effects on neurotransmitters, the diarrhea some users experience (esp. when they take it without food) and the fact that many, but by far not all studies confirmed direct inusulin sensitizing effects of taurine are the reason I'd still classify it as [B] level supplement - certainly one of the better ones, but still only "possibly beneficial".

• 

  Table 1: Within group changes in randomized controlled GTE supplementation study involving 20-65 year old type 2 diabetics with BMI > 25 kg/m² (Hsu. 2012)

  Green tea extract [C]: GTE can help with insulin sensitivity in two different ways. Firstly, it will help control the inflammatory processes that are (partly) responsible for the development of insulin resistance and it will secondly help you to "cut carbs" by simply blocking their digestion and assimilation (Forester. 2012; Williamson. 2013).
  
  And while the real world benefits of GTE supplementation in a 2012 study by Hsu et al. were not statistically significant, it may still be worth trialling a dose of 3x 200-500mg per day. That being said, unless you are specifically looking for the stimulant effects of GTE, you should consider using a decaffeinated extract because you do not really need the additional caffeine (cf. part I of this series). 
  
  The reason I still classified GTE as [C] as in "marginally useful" is that the study by Hsu is not the only human trial that did not find significant effects on insulin sensitivity. It is rather one of the few where you could actually argue that - though not significant - it may have had an independent effect on glucose management. In the majority of studies "green tea exhibited limited benefits in reducing FBS or HbA1c levels" and as Ruitang Deng puts it in his recent review: "Should not be recommended for managing hyperglycemia." (Deng. 2012) This does not mean that it cannot help ameliorate the side effects, but we are looking for agents that will actually help you lower your blood glucose levels and in this regard green tea extracts are only marginally useful.

• 

  Amla, gooseberry, or Emblica Officinalis call it whatever you want, but don't expect too much - it may work, but it's no comparison to the [A]-class supplements. Moreover, the results from the available human study could be distorted by additional ingredients in the supplement formulas the scientists used.

  Gooseberry (emblica officinalis) [C]: Studies by Mitra (2007), Faizal (2009), Iyer (2009) and Chen (2011) all provide evidence that the ingestion of extracts from Indian gooseberry (=Amla), an edible fruit from trees of the phyllanthaceae family can effectively improve blood glucose management.
  
  Due to the fact that the Gooseberry extract was administered in conjunction with other agents, it is however difficult to suggest an effective dosage, but it appears as if 100-150mg per day of gooseberry extract would be enough.
  
  In Iyer et al. even a single serving of fresh amla (~35g) got the job done, but the overall effect size is rather mediocre, thus Gooseberry is only "possibly useful" [C]. 
• Fenugreek [B]: Also known as trigonella foenum-graecum L., fenugreek belongs to the plant family fabaceae (or leguminosae).
  
  

  

  Figure 3: Relative changes in response to glucose challenge (glucose AUC, glucose half-life and metabolic clearance rate) in 5 non-insulin dependent diabetic patients after consuming a diet supplemented with 25 g fenugreek seeds daily for 15 days; the data is expressed relative to the values the scientists measured in five likewise diabetic control subjects (Raghuram. 1994)

  Fenugreek seeds and extracts from the leaves have a decent amount of studies to support its anti-hyperglycemic effects - including clinical studies with human volunteers showing that dosage of only 500 mg of seed or leaf extracts given once or twice daily either alone or in combination with standard, synthetic anti-diabetic drugs such as metformin and glipizide provided beneficial effects on controlling plasma glucose levels (Deng. 2012).
  
  The reason I'd still classify it as [B] are (a) the fact that it takes a huge amount of the seeds (e.g. 25g; see figure 3) to elicit significant effects and (b) the fact that studies using extracts yielded ambiguous results. Contrary to the whole seeds, of which it seems that they exert their beneficial effects by similar mechanisms as dietary fiber, leaf extracs appear to exert a direct insulin sensitizing effect.
  
  In a study by Abdel-Barry et al. from the year 2000, 40 mg/kg aqueous extract powder from fenugreek leaves(!) in 10 mL distilled water lowered the glucose levels of 20 healthy male volunteers aged 20-30 years by 13.4% 4h after ingestion. Unfortunately, the hunger, frequent urination and dizziness one third of the subjects complained about, was not the only side effect - the subjects also had significantly reduces serum potassium levels; an observation of which the researchers rightly state that it warrants further investigation to ensure the long-term safety of fenugreek leaf extracts.
  
  Bottom line? Well, once again "possibly useful", but only if you actually have problems with insulin resistance and high blood sugar.

"What? Where is there rest?" In case this is pretty much what you are thinking right now, I can calm you down, there will be at least another serving of pro-insulin sensitivity supplements. I simply don't have the time to write more today, but did not want to go back on my promise from last Sunday. So, be patient, there is going to be more: Promising supps such as cinnamon, vinegar, or grape seed extract, for example but also questionable stuff such as bitter melon or legume extracts.

References: 

• Abdel-Barry JA, Abdel-Hassan IA, Jawad AM, al-Hakiem MH. Hypoglycaemic effect of aqueous extract of the leaves of Trigonella foenum-graecum in healthy volunteers. East Mediterr Health J. 2000 Jan;6(1):83-8.
• Anděl M, Skrha P, Trnka J. [Metformin: the overlap of diabetology and oncology]. Vnitr Lek. 2013 Aug;59(8):738-42. 
• Boulé NG, Kenny GP, Larose J, Khandwala F, Kuzik N, Sigal RJ. Does metformin modify the effect on glycaemic control of aerobic exercise, resistance exercise or both? Diabetologia. 2013 Aug 23. 
• Brøns C, Spohr C, Storgaard H, Dyerberg J, Vaag A. Effect of taurine treatment on insulin secretion and action, and on serum lipid levels in overweight men with a genetic predisposition for type II diabetes mellitus. Eur J Clin Nutr. 2004 Sep;58(9):1239-47.
• Cavagnini F, et al. Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man.Metabolism. 1982; 31:73–77. 
• Chen TS, Liou SY, Wu HC, Tsai FJ, Tsai CH, Huang CY, et al. Efficacy of epigallocatechin-3-gallate and amla (Emblica officinalis) extract for the treatment of diabetic-uremic patients. J Medicinal Food. 2011;14:718–23.
• Dalaklioglu S, Kuscu N, Celik-Ozenci C, Bayram Z, Nacitarhan C, Ozdem SS. Chronic treatment with taurine ameliorates diabetes-induced dysfunction of nitric oxide-mediated neurogenic and endothelium-dependent corpus cavernosum relaxation in rats. Fundam Clin Pharmacol. 2013 Jun 14. 
• Deng R. A review of the hypoglycemic effects of five commonly used herbal food supplements. Recent Pat Food Nutr Agric. 2012 Apr 1;4(1):50-60.
• El Zahraa Z El Ashry F, Mahmoud MF, El Maraghy NN, Ahmed AF. Effect of Cordyceps sinensis and taurine either alone or in combination on streptozotocin induced diabetes. Food Chem Toxicol. 2012 Mar;50(3-4):1159-65. 
• Faizal P, Suresh S, Satheesh Kumar R, Augusti KT. A study on the hypoglycemic and hypolipidemic effects of an ayurvedic drug Ra-janyamalakadi in diabetic patients. Indian J Clinical Biochem. 2009;24:82–7.
• Mitra A. Effects of a composite of tulsi leaves, amla bitter gourd, gurmur leaves, jamun fruit and seed in type 2 diabetic patients. J Clinical Diagnostic Research. 2007;6:511–20.
• Forester SC, Gu Y, Lambert JD. Inhibition of starch digestion by the green tea polyphenol, (-)-epigallocatechin-3-gallate. Mol Nutr Food Res. 2012 Nov;56(11):1647-54.
• Franconi F, Bennardini F, Mattana A, Miceli M, Ciuti M, Mian M, Gironi A, Anichini R, Seghieri G. Plasma and platelet taurine are reduced in subjects with insulin-dependent diabetes mellitus: effects of taurine supplementation. Am J Clin Nutr. 1995 May;61(5):1115-9.
• Franconi F, Di Leo MA, Bennardini F, Ghirlanda G. Is taurine beneficial in reducing risk factors for diabetes mellitus? Neurochem Res. 2004 Jan;29(1):143-50.
• Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999 Aug;27(3-4):309-14.
• Hansen SH. The role of taurine in diabetes and the development of diabetic complications. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):330-46. 
• Hsu CH, Liao YL, Lin SC, Tsai TH, Huang CJ, Chou P. Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebo-controlled clinical trial. Altern Med Rev. 2011 Jun;16(2):157-63.
• Imae M, Asano T, Murakami S. Potential role of taurine in the prevention of diabetes and metabolic syndrome. Amino Acids. 2012 Dec 8.
• Ito T, Schaffer SW, Azuma J. The potential usefulness of taurine on diabetes mellitus and its complications. Amino Acids. 2012 May;42(5):1529-39. doi: 10.1007/s00726-011-0883-5. Epub 2011 Mar 25.
• Iyer U, Joshi A, Dhruv S. Impact of Amla (Embilica Officinalis) supplementation on the glycemic and lipidemic status of type 2 diabetic subjects. J Herbal Medicine and Toxicol. 2009;3:15–21.
• Khamaisi M, Rudich A, Potashnik R, Tritschler HJ, Gutman A, Bashan N. Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats. Metabolism. 1999 Apr;48(4):504-10.
• Kim SJ, Ramesh C, Gupta H, Lee W. Taurine-diabetes interaction: from involvement to protection. J Biol Regul Homeost Agents. 2007;21(3-4):63-77.
• Kim KS, Oh da H, Kim JY, Lee BG, You JS, Chang KJ, Chung HJ, Yoo MC, Yang HI, Kang JH, Hwang YC, Ahn KJ, Chung HY, Jeong IK. Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes. Exp Mol Med. 2012 Nov 30;44(11):665-73.
• Lautatzis ME, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: A systematic review. Metabolism. 2013 Jul 22. 
• Li C, Cao L, Zeng Q, Liu X, Zhang Y, Dai T, Hu D, Huang K, Wang Y, Wang X, Li D, Chen Z, Zhang J, Li Y, Sharma R. Taurine may prevent diabetic rats from developing cardiomyopathy also by downregulating angiotensin II type2 receptor expression. Cardiovasc Drugs Ther. 2005 Mar;19(2):105-12.
• Mitra A. Effects of a composite of tulsi leaves, amla bitter gourd, gurmur leaves, jamun fruit and seed in type 2 diabetic patients. J Clinical Diagnostic Research. 2007;6:511–20.
• McNeilly AM, Davison GW, Murphy MH, Nadeem N, Trinick T, Duly E, Novials A, McEneny J. Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance. Lipids Health Dis. 2011 Nov 22;10:217.
• Nawaz FH, Khalid R, Naru T, Rizvi J. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome? J Obstet Gynaecol Res. 2008 Oct;34(5):832-7. 
• Porasuphatana S, Suddee S, Nartnampong A, Konsil J, Harnwong B, Santaweesuk A. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study. Asia Pac J Clin Nutr. 2012;21(1):12-21. 
• Raghuram TC, Sharma RD, Sivakumar B, Sahay BK. Effect of fenugreek seeds on intravenous glucose disposition in non-insulin dependent diabetic patients. Phytotherapy Research. 1994;8:83–6.
• Schaffer SW, Azuma J, Mozaffari M. Role of antioxidant activity of taurine in diabetes. Can J Physiol Pharmacol. 2009 Feb;87(2):91-9.
• Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11692-7.
• Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA, Kaufman DL. GABA regulates both the survival and replication of human ss-cells. Diabetes. 2013 Aug 30. 
• Williamson G. Possible effects of dietary polyphenols on sugar absorption and digestion. Mol Nutr Food Res. 2013 Jan;57(1):48-57.
• Xiang G, Pu J, Yue L, Hou J, Sun H. α-lipoic acid can improve endothelial dysfunction in subjects with impaired fasting glucose. Metabolism. 2011 Apr;60(4):480-5.
• Yao HT, Lin P, Chang YW,Chen CT, Chiang MT, Chang L, Kuo YC, Tsai HT, Yeh TK. Effect of taurine supplementation on cytochrome P450 2E1 and oxidative stress in the liver and kidneys of rats with streptozotocin-induced diabetes. Food Chem Toxicol. 2009 Jul;47(7):1703-9

On Short Notice: Teas & Prostate, Metformin & Amenorrhea, Stevia & High, Omega-3 & Low Cortisol, Aminos & Weight Control, Nordic Hamstring Exercise & 20% More Power!

Image 1: This would be a case where metformin probably won't help you to get your menses back - unless this is just one of your "yous" and you are taking high doses of anti-psychotics, of course.

In view of the fact that I have piled up way more "On Short Notice" items than I can possibly squeeze into one installment, today's news on the right tea (green or black) for prostate cancer, the purported anti-obesity effects of leucine and alanine, which turn out to be inferior to those of whole protein, the anti-amenorrhea and weight loss effects of metformin in women on anti-schizophrenic drug and how this relates to PCOS, the surprising N=1 cortisol-raising, high blood pressure and water retaining effects of stevia, the stress and weight loss reducing effects of omega-3s and high DHA levels in the brain, and an effective yet rarely used hamstring exercise, the "Nordic hamstring exercise", will be complemented by another installment of "On Short Notice" either tomorrow (in case I don't find the time to write the next installment of the Circadian Rhythm Series) or earlier next week... but enough of these organizational matters, let's see what we have in stock, here:

• Differential effects of green and black tea on prostate cancer risk While we are, yet again, only dealing with epidemiological shenanigan in a population living in a, if not the juggernaut of the far east, the >50% increase in hazard risk in the 27,293 men from the Singapore Chinese Health Study Julia A. Montague and her colleagues report for men who drink 1 cup of black tea per day is somewhat alarming (Montague. 2012). The fact that the hazard risk decreases to +17% with more than 2 cups of black tea does yet suggest that this is nothing but a statistic outlier. That said, black tea is (at least based on the results of this study) overall probably as benign as green tea, which is totally devoid of statistical beneficial or detrimental effects on prostate cancer risk in this cohort of normal-weight men in their middle to late 50s.
  This result does by the way not conflict with previous research, which did - if anything - only suggest a "borderline significant" beneficial effect of green tea and absolutely no effect of black tea on prostate cancer risk (Zheng. 2012). Apropos prostate cancer, just in case you missed it I highly suggest you take a look at my brief write-up on the recently published "red meat will give you prostate cancer study" before you decide on whether or not you got to stop eating meat for the sake of your prostate.

• 

  Figure 1: If  ~50g of leucine and alanine /kg chow are good, then 500g of whey are magic; makes you wonder, why you would want to add just one amino acid, instead of more protein, no?

  "Dietary L-leucine and L-alanine supplementation have similar acute effects in the prevention of high-fat diet-induced obesity",  that's the somewhat ill-chose title of a recently published paper by Anne Freudenberg, Klaus J. Petzke, Susanne Klaus from the German Institute of Human Nutrition in Potsdam-Rehbruecke which does not show that the ingestion of l-leucine or alanine, but rather an isocaloric high protein diet version of the high-fat diets the researchers fed their 10-week-old male C57BL/6 mice, prevented them from getting obese (Freudenberg. 2012).
  While the high fat + complete protein mice hardly gained any body fat, the high fat + leucine and high fat + alanine (both diets were "adequate" in protein and contained 100g whey + 60g leucine and 100g whey + 45g alanine, respectively)  got only significantly less fat compared to their peirs on the 100g whey only diet control HFD diet. Now, the high protein mice (500g of whey per kg chow; =5x over baseline) simply consumed less energy, but so did the mice on the leucine and alanine enhanced diets, so that the title of the study is not just misleading, it also disguises the most important result of the study, which is high protein diets keep mice lean.
• "Cure-it-all-drug" metformin helps with anti-psychotic induced amenorrhea and weight gain, as well. If metformin was not (a) no longer protected by patent rights and (b) would not basically work via similar mechanisms as exercise I would really begin to smell fraud over the ever-extending list of pathologies this 1920s medication is good for (this is when it was originally discovered, it took however until 1958 before researchers realized the potentials and a pharma company introduced it to the UK market). New to the list are the negative side-effects women experience in response to anti-psychotic treatments. In a recently documented experiment, 48 women (ages 18-40 years) with amenorrhea and weight gain in response to clozapine, olanzapine, risperidone, or sulpiride (all anti-psychotic drugs administered to treat schizophrenia) received a dose of 1,000mg of the wonder-molecule per day (Wu. 2012). After 2 months 25% of the women had resumed menstruation, after another 2 weeks it were 80% and after 3 months all women were eumenorrheic, again (of the placebo group only 2 resumed menstruating). Instead of gaining another 2kg of body weight, they had lost 2kg and the previously thwarted prolactin, LH, and testosterone levels, as well as the LH/FSH ratio had normalized.
  Probably, some of you may now ask themselves: Will this work for me as well - though I am not taking anti-psychotics? I would love I could answer this question, but aside from polycystic ovarian syndrome (PCOS), where we have a couple of trials in which metformin was used with success (cf. Velazquez. 1998; Bela. 2009; Palomba. 2009), the scientific evidence is scarce and in view of the fact that we know even less about the underlying mechanisms by which risperidone & co cause amenorrhea and weight gain than about the almost magical omnipotence of metformin I honestly can't tell. One thing that comes mind, where metformin is yet very unlikely to of any use is diet or exercise induced amenorrhea (overtraining and undereating), because this form of amenorrhea presents with a totally different hormonal profile, with low levels of basically all reproductive hormones.
• Stevia as cortisol promoter? Case study: Bloating, high blood pressure and malaise in a young previously healthy woman. Before I go on, let me briefly remind you that the events that are described in a recent case report from the University of Iowa Hospitals and Clinics may should be regarded with the degree of caution that is indicated whenever we are talking about case reports, specifically because stevia does actually have a pretty decent safety profile (aside from the occasional allergic reactions you will see with almost every foreign molecule you put into your body, obviously).

  

  Figure 2: If you block the 11bHSD2 enzyme that will convert cortisol into inactive cortisone, you are in trouble and a bloated tummy is certainly your least problem, not because "cortisol is bad", as common sense would dictate, but because not being able to manage it is bad (img. Michael. 2008)

  When a 32 year old Caucasian woman presented with generalized edema (feet, hands and face) that had persisted for over six months at her Dr office and was found to to suffer from pre-hypertension (138/88 mmHg) and hypokalemia (3.4 mM/l) that was brought about by a decline in serum aldosterone and plasma renin activity and corroborated by a concomitant  increase in the plasma cortisol/cortisone ratio, most Dr.'s would probably have thought of licorice intoxication. As it turned out, it were neither the glycyrrizinic acid, not the glycyrrhetinic acid from licorice which brought about these problem, but rather the stevia the lady had been using for over 9 months, now. Obviously, the sweetener (from an undisclosed brand) had blocked the 11 beta-hydroxysteroid dehydrogenase Type 2 (11-beta-HSD 2, see figure 2) enzyme that's responsible for the conversion (="deactivation") of cortisol to cortisone - with all the negative side effects of the subsequent 12x elevation of the ratio of active to inactive corticosteroids (Esmail. 2012).
  Now, I am certainly not suggesting that this is going to happen to everyone, but it could well be that the frequent reports of headaches people are developing after a couple of days "on stevia", could also be related to the effects the sweetener has on people with a certain genetic disposition. So, if you get a headache or start holding water like crazy, when you use stevia / stevia sweetened products, first try using a different brand (there have been issues with toxins in some products), make sure you have a pure stevia sweetener and not one with other sweeteners added (thx. to Amit for the reminder about erythritol that's in many products), switch to another preparation, e.g. from pure stevisoids to a a more "natural" extract and if all that does not help, just turn your back on it - you can live without it, I guarantee ;-)
• Omega-3's modulate adrenal activity What many people know from going overboard on fish oil has now been established in a recently published rodent study by Marie Hennebelle and her French (resident) colleagues (Hennebelle. 2012). The researchers fed a group of rodents a totally ALA free energetically restricted diet to produce male rats with brain phospholipid DHA levels that were 50% lower than those of the normal control. The 6 month-old rodents were then subjected to chronic restraint stress (6 h/d) for 21 days. As expected the rodents on the alpha linolic acid deficient diets had a much harder time coping with the torture they were exposed to and showed higher corticosterone levels, more pronounced behavioral abnomalies and slightly more pronounced weight loss in the 3-4 week of the 1-month experimental period. What's intriguing though is the the remarkable stress resistance (one could also say adrenal hypofunction ;-) in the rodents in a third experimental group, who had received an omega-3 enriched diet that boosted their brain DHA levels to 10% above normal: Compared to both the normal, as well as the omega-3 deprived rodents they had ~30% lower cortisol levels during week two and three of the experiment and lost only 50% of the weight their normal and ALA deprived peers did.
  That this is not necessarily a good thing for everyone is probably nothing I have to tell you. After all, the number of people who are hardly functioning due to over-supplementation with fish oil and (as this study would suggest) below normal stress responses is ever increasing. As with so many nutrients and supplements, it thus comes down to specificity and hitting the right ratios for you as an individual, again. And what's most important: Before you even start thinking about "fixing your adrenals" you should first take a look at the various stressors in your life. After all, the aforementioned fatigue is not simply a result of two much fish oil, but of its combination with a lifestyle which simply requires a robust and healthy cortisol response. You would not smoke weed to calm yourself down minutes before running away from a saber-toothed tiger, either, would you?

• 

  Video 1: These young ladies show you how it's done - well almost, you better go a little slower (click image to watch.

  Scientists confirm efficacy of nordic hamstring exercise - up to +20% increase in peak torque! What? You don't know the nordic hamstring exercise - I bet you do, but probably not by this name. Check out video 1 to the right and you will know what the 18 male players from a club in the English professional soccer leagues (mean±SD; age, 22.9±3.6 years; stature, 1.81±0.08 m; body mass 78.0±9.7 kg) did for 1x 2x5, 2x 2x6, 3x 3x6 and 3x 3x8 (sessions per week x sets x reps) during week 1-4 of the study period to improve their peak torque by up to 21% in all assessment conditions (90-61°, 60-31° and 30-0° of knee extension; cf. Iga. 2012).
  What is yet important is that you stick to an adequate temp and don't mess around and hurt yourself. In the study at hand, the velocity of the movement was standardized to 30°/s. If we assume that you go over the full ROM it must therefore take you 3s until your nose hits the ground (if you are afraid to hurt your nose, you may be interested in the SuppVersity EMG Series and the Best Leg + Hamstring Exercises ;-)

I hope you enjoy this more digestible format, having 20 of these items in one installment is - at least in my view - somewhat beside the point. Not that this would not be possible, but if I go by the average attention span of my real-life students, multiply it by 2x to accommodate for your superior cognitive abilities and personal interest in the topic, it appears prudent to call it a day for today. And if can't stand the 24h for the next SuppVersity news to be released, I suggest you simply like the SuppVersity Facebook Wall, where you will find another seven allegedly shorter news-items... about the wheat-allergens in soap (+ scary pic of what can happen, when you use those), for example or the news photo-based cholesterol test (a photo of your hands is all it takes), which is probably going to give the sales of statins another boost.

References:

• Billa E, Kapolla N, Nicopoulou SC, Koukkou E, Venaki E, Milingos S, Antsaklis A, Adamopoulos DA. Metformin administration was associated with a modification of LH, prolactin, and insulin secretion dynamics in women with polycystic ovarian syndrome. Gynecol Endocrinol 2009; 25:427–434
• Esmail S, Kabadi UM. Edema, Enigma: 11 B-Hydroxysteroid dehydrogenase Type 2 Inhibition by Sweetener “Stevia”. Open Journal of Endocrine and Metabolic Diseases, 2012, 2, 49-52.
• Freudenberg A, Petzke KJ, Klaus S. Dietary L-leucine and L-alanine supplementation have similar acute effects in the prevention of high-fat diet-induced obesity. Amino Acids. 2012 Jul 31.
• Hennebelle M, Balasse L, Latour A, Champeil-Potokar G, Denis S, Lavialle M, Gisquet-Verrier P, Denis I, Vancassel S. Influence of omega-3 Fatty Acid status on the way rats adapt to chronic restraint stress. PLoS One. 2012;7(7):e42142.
• Montague JA, Butler LM, Wu AH, Genkinger JM, Koh WP, Wong AS, Wang R, Yuan JM, Yu MC. Green and black tea intake in relation to prostate cancer risk among Singapore Chinese. Cancer Causes Control. 2012 Aug 3.
• Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev 2009; 30:1–50
• Wu RR, Jin H, Gao K, Twamley EW, Ou JJ, Shao P, Wang J, Guo XF, Davis JM, Chan PK, Zhao JP. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2012 Aug 1;169(8):813-21. 
• Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure while facilitating normal menses and pregnancy. Metabolism 1994; 43:647–654
• Zheng J, Yang B, Huang T, Yu Y, Yang J, Li D. Green tea and black tea consumption and prostate cancer risk: an exploratory meta-analysis of observational studies. Nutr Cancer. 2011;63(5):663-72.

Tangeritin, Natural Metformin from the Rind of Mandarin Oranges Hits the OFF-Switch on Diet Induced Obesity

Image 1: Tell me the truth! How much "natural metformin" did you throw away with those mandarine rinds in your life? Update (08/11/2012) Scroll down to the red box on dosing, I added, to check out why you better start saving your mandarine rinds now to be able to do a "tangeritine cycle" in a couple of years ;-)

I guess it is about time for another longer post on the "Supp" part of SuppVersity and what would be better suited than providing my readers from inside the business to spice up their #1 selling product which has as of late lost yet two other "all natural" ingredients in the never-ending arsenal of funky herbs, spices, -amines and -ephrines. Luckily the supplies nature has in stock are endless and with 5, 6, 7, 8, 40-pentamethoxyflavone (I am not kidding, now that 1,3 DMAA is gone, you will have to remember a couple more numbers ;-) the "next big" thing that's ready to get out of the starting blocks could actually prove to be more than just a stim and an actual weight loss adjuvant! After all, the AMPK boosting effects of tangeretin, which is abundant in the rinds of citrus fruits, such as mandarin orange, rutaceae and yuhu in Korea, appear to be everything but "ordinary" and they are not even the most interesting effect this compound may have on your metabolism.

Tangeritin, is not be be confused with citrus aurantium, is no stim and could thus actually work!

In a paper that has recently been published in the Journal of Molecular and Cellular Endocrinology Kim et al. report that the administration of of 200mg/kg (human equivalent 1.3g) of tangeritin per day to mice on a high fat diet did not only slow down weight gain and the development of glucose intolerance and hypercholesterolemia, but also had beneficial modulatory effects on the secretion of the adipokines adiponectin, leptin and resistin, as well as the release of IL-6 and MCP-1.

Figure 1: Adipocytokine expression and body weight gain of mice after 27 and 55 days on control, high fat (HFD) or high fat diet with 200mg/kg tangeritin (HFD + 200Tan; left) and in vitro glucose uptake of isolated myocytes upon incubation with tangeritin at doses of 25, 50 and 100mMol (right; data adapted from Kim. 2012)

For Kim et al. the profound effects wich lower leptin, aidponectin, resistin and IL-6 expression in the HFD + Tangeritin group than in the control (I wish we had the body fat levels, I am curious if those were not lower with HFD + tangeritin than in the control group, as well) did yet not come as a surprise.

Additional figure: How much rind (in g) do you need to produce 1g of tangeritin by water extraction at different temperatures and extraction times (data calculated based on Xu. 2012)

Update (08/11/2012): In response to questions both on Facebook as well as in the comment section I have compiled the graph on the right, which shows you how much rind (in grams) you need if you wanted to water-extract your 1g daily dose of tangeritin from Satsuma mandarin, which is probably the type of mandarin that is most widely sold here in the West and the more exotic, but tangeritin-rich Ponkan. If you take a closer look at the data from Xu et al. you will yet have to acknowledge that it is probably not feasible to produce your own extract at home - even if you you managed to extract ALL the tangeritin from the Ponkan, which obviously won't work by simply cooking it up, you would still need 232g of rind per day!

In previous in vitro experiments on isolated muscle cells (C2C12 myotubes), the researchers had already established that tangeritin, when it is appropriately dosed (!), exerts extraordinary powerful effects on the expression of the energy sensor and metabolic switch AMPK, which has as of late gotten quite some attention in  the laypress as the target for "the exercise pill", the "ultimate antiobesity + antidiabetes pill", the "anticancer and longevity pill",... well basically everything that could make a respective drug a pharmacological "bockboster" (read more about AMPK in the SuppVersity Intermittent Thougths Series: "The AMPK/mTOR Seesaw".

Figure 2: Hand in hand with the beneficial effects on adipocytokine production, the addition of tangerine to the high fat diet also ameliorated the growth and necrosis of adipocytes (Kim. 2012)

They also knew from previous studies that aside from its role as an inducer of AMPK and GLUT-4 expression in the muscle tissue, tangeretin posses anti-cancer, anti-oxidant and anti-inflammatory properties, as well (Yoon. 2011; Xu. 2008). Kim et al. also point out that

In addition to its anti-oxidant effects, tangeretin has been reported to inhibit the growth of hepatocytes both in vitro and in vivo via inhibition of mTOR/p70S6 kinase (Cheng. 2011). Regarding tangeretin-mediated effects on neuronal disease, a number of studies have shown that tangeretin reduces dopaminergic neurotoxin-induced neuronal injury and prevents tunicamycin-induced cell death in mice through an increase in glucose-regulated protein (GRP)78 and heme oxygenase (HO)-1 expression in renal tubular epithelium (Takano. 2007).

Moreover, another recent study by Choi et al. reports that tangeritin also has protective effects against the lipopolysaccharide (LPS) induced nitric oxide (NO) expression in the digestive tract and could thus offer acute and chronic protection from LPS induced cell damage (Choi. 2007).

Awesome? Well, in a way it may be, but in the end most of what we see is a result of pushing the right switches and in this regards tangeritin appears to be outstandingly good - for a supplement to say the least; that you don't need exercise in a pill if you hit the gym three to five times a week and lead an active life is something I don't have to tell you anyway, right?

Figure 3: Unlike thiazolidinedione like Rosiglitazone and "harmless" health supplements as fish oil (Neschen. 2006) tangeritin does not work its antihyperlipidemic (=triglyceride lowering) and anti-hyperglycemic (=blood sugar lowering) effects effects by inducing PPAR-gamma and thus allowing your body to stash away even more energy as body fat. On the contrary, reduces ppar-gamma expression and consequently stops the expansion of adipose tissue even in the presence of a hypercaloric high fat diet (cf. figure 1, tissue samples) - the beneficial effects of PPAR-gamma blockade have only recently been investigated by Lohdi et al. who call it an "off switch" for diet induced obesity (Lohdi. 2012).

Implications: Now, we are certainly not dealing with the "supplemental reinvention of the wheel here", and still: The effect size in the Tan200 group was so pronounced that I felt that the news on tangeritin, which had originally been part of last weeks "On Short Notice" deserved it's own post - not the least, because  it will not have you pay dearly for the improved glucose tolerance and lower blood lipid levels as thiazolidinediones like Rosiglitazone and even fish oil, both of which have been shown to reduce serum glucose and triglyceride levels via PAR-gamma dependent mechanisms (figure 3; specifically for fish oil Neschen. 2006) and thusly promote not block fat loss. Tangeritin, on the other hand decreases the PPAR-gamma activity and therefore acts as an "off-switch" for dietary induced obesity (Lohdi. 2012) .

Moreover, the reduced obesity was not a mere side effect of a loss of appetite and subsequent anorexia. The animals in the HFD and the HFD + Tan200 group consumed the exact same amount of chow - with the one small but absolutely critical difference that the rodents in the Tan200 group did not store the superfluous energy as body fat. It is this "anti-fat" effect which is not borne by negative health effect as it is the case for conjugated linoleic acid (CLA), for example (cf. "CLA Destroys Body Fat") which makes tangeretin a very interesting candidate for a weight loss supplement for both obese and lean dieters and, when I come to think about it, probably even for people who want to bulk.

There are however a few potential downsides and questions that remain to be answered before we celebrate the advent of yet another "next big thing" that will then line up with the rest of the supplemental non-starters:

• First of all, the mechanism of action does remind me of alpha lipoic acid (ALA), which is still a very good supplement for obese or at least insulin resistant dieters, but turned out to be useless, even potentially counterproductive in exactly those lean selectively (muscle) insulin sensitive athletes it is currently heavily marketed to as "repartitioning agent" (see "Lean and Muscular With Alpha Lipoic Acid?"). So the question is: "Is tangeritin only another ALA?" Is it better or worse and will it work fr lean people as well as it did for the mice on the obesogenic diet in the study at hand?
• Secondly, despite the fact that tangeritin acts in an almost metformin-esque fashion via AMPK and PGC-1alpha, which is much more likely to work in humans as well than your usual beta-3 agonist (e.g. synephrine) or other thermogenic with promising rodent data and absolute no effects in human beings, we still need controlled human trials to see whether or not this nquestionably promising flavenoid does work in humans at all.
• And thirdly, in view of the fact that only the high dose tangeritin (100mMol) elicited a pronounced increase in glucose uptake in the in-vitro study (cf. figure 1), it will be of utmost importance that future supplements or pharmacological agents are appropriately dosed - and we all know that this is in 90% of the cases where the raw material is more expensive than caffeine anhydrous simply not the case. 

That said, I would venture the guess that (assuming one of the smaller supplement companies finds a bulk supplier in China) we are going to see "Tange(R)iburn" or a tangerine based substrate repartitioning agent (after all those sell pretty well, too) in the near future - before anyone has a clue what dosages will be necessary to see beneficial effects and probably with way less than the 1g+ of tangeritin in it than Kim et al.'s results would suggest as a minimal daily dose for an adult to see similarly outstanding results as our hairy friends in the study at hand.

References

• Cheng Z, Surichan S, Ruparelia K, Arroo R, Boarder MR. Tangeretin and its metabolite 4'-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K. Br J Pharmacol. 2011 Apr;162(8):1781-91.
• Choi SY, Ko HC, Ko SY, Hwang JH. Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol. Pharm. Bull. Choi, S.Y., Ko, H.C., Ko, S.Y., Hwang, J.H., 2007. Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol. Pharm. Bull. 30, 772–778.; 30, 772–778. 
• Lodhi IJ, Yin L, Jensen-Urstad AP, Funai K, Coleman T, Baird JH, El Ramahi MK, Razani B, Song H, Fu-Hsu F, Turk J, Semenkovich CF. Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARγ Activation to Decrease Diet-Induced Obesity. Cell Metab. 2012 Aug 1.
• Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S, Gillum M, Shulman GI. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes. 2006 Apr;55(4):924-8. 
• Kim MS, Hur HJ, Kwon DY, Hwang JT. Tangeretin stimulates glucose uptake via regulation of AMPK signaling pathways in C2C12 myotubes and improves glucose tolerance in high-fat diet-induced obese mice. Mol Cell Endocrinol. 2012 Jul 6;358(1):127-34. 
• Takano K, Tabata Y, Kitao Y, Murakami R, Suzuki H, Yamada M, Iinuma M, Yoneda Y, Ogawa S, Hori O. Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. Am J Physiol Cell Physiol. 2007 Jan;292(1):C353-61.
• Xu HG, Chen CJ, Liu DH, Minerals, phenolic compounds, and antioxidant capacity of citrus peel extract by hot water. J. Food Sci. 2008; 73, C11–C18. 
• Yoon JH, Lim TG, Lee KM. Tangeretin reduces ultraviolet B (UVB)-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking mitogen-activated protein kinase (MAPK) activation and reactive oxygen species (ROS) generation. J. Agric. Food Chem. 2011; 59, 222–228