Science Round-Up Seconds: Prostate Cancer Special - Are You Going to Die From or With Prostate Cancer? Plus: What Can be Done to Influence This Fate?

Today's SuppVersity article revolves around the question what YOU can do to make sure that the procedure this guy is about to endure is the only thing to be afraid of, when you are going to your check ups ;-)

Let me just get this out there, if you missed an appointment because you were listening to the show live, yesterday, I am sorry. Carl and I actually went "longer than long". What was originally intended to be a one hour show did end being a 125min podcast. That being said, there is little left for the "Seconds" - at least news-wise. So, I decided to kick off today's installment of the traditional SuppVersity Science Round Up Seconds with a quick hit summary of the bottom line of the show. As far as the details are concerned, I would strongly encourage you to download and listen to the podcast. I am not the one to call his own stuff "highly educational", but I guess even those of you who are already well-versed in this issue will find one or another useful bit of information...  

Apropos useful, if you asked me about the one thing you can do to ward off prostate cancer my answer would be "turn to physical culture". Whether you are at risk of developing a form of prostate cancer (PCa) that will have you die or at least suffer from the disease, everybody has in mind, when he thinks about PCa, will not depend on doing A and not doing B. It's, just as so often, a matter of checks and balances. And the things you got to balance are

• 25% of cancer cases globally are due to excess weight and a sedentary lifestyle. (McTiernan. 2008)
  diet,
• exercise,
• sleep, and
• sun exposure

These are the fundamentals and things may in fact be less complicated than many of the numbers I mentioned earlier in the show would suggest. Ok, there is ...

• Don't ignore this post if you are a woman. Most, if not all of the things that help men ward off prostate cancer will also help women to reduce their risk of developing breast and other forms of cancer. A whole foods diet, a reasonable amount of exercise, a lifestlye that tailors to your natural circadian rhythm (learn more) and allows for adequate amounts of quality sleep (7h+ every night) are a MUST for both, women and men who are concerned about developing any form of cancer.
  

  In fact, the way these parameter changed in the course of the last century, is probably the most likely explanation why you may get the impression that developing some sort of cancer is about to become the new normal.
  a 40% risk reduction in advanced PCa for white men consuming a high amount of fruits,
• much to my own surprise no conclusive evidence that veggies are only half as protective as most of us probably thought they would be (think about the heavily advertised effect of DIM in cruciferus vegetables, for example.
• the thing about dairy in whites and meats in black increasing the overall prostate cancer risk by 70% and 80-90% (all meats vs. red meats), respectively
• the "problem" with only whole tomatoes being associated with significant risk reductions and the failure of tomato sauce (likewise pimped as a savior of the average American's prostate in the media) to elicit any effect on the health of your prostate
• an undebatable increase in cancer risk with increasing food consumption (+100% in the third tertile, Rohan. 1995)
• a non-significant association with the risk of developing prostate cancer with high intakes of vegetable oils (+24%; Rohan. 1995)
• a protective effect of saturated fats (-52%; Rohan. 1995) that appears to depend on the population you are analyzing (and I suppose the bias with which you approach the data)
• the protective power of real vitamin A (retinol; -34% for high(er) intakes. Rohan. 1995) and the absence of the latter for carotenes
• etc.

but in the end, all this tapers towards one thing - a dietary prescription that is not much different from the one you read about here at the SuppVersity on an almost daily basis. It is a balanced whole foods diet that is based on a reasonable baseline intake of carbohydrates, proteins and fats. A diet that puts an emphasis on ratios, not total amounts and above all a diet that is able to promote overall health - in mainstream terms, a mixture of the best principles from the two best-established "anti-cancer" diets yielding something you may want to call a Mediterranean, paleo-esque diet.

What's the role of supplements here?

Despite the fact that the word "supplement" already implies that these agents are nothing that's intended to treat, cure and replace, the shiny adds of the multi-billion dollar industry does suggest just that: Don't be fooled. There is probably use in supplements such as

• the usual suspects: lycopene, ginger, pomegrenate, garlic, green tea, curcumin, resveratrol, grape seed extract, milk thistle, DIM,
• methyldonors (choline, betaine, SAM, etc.) and molecules that are important for the optimal function of the methylation cycle (B6, B12, etc.)
• mitochondrially targeted anti-oxidants like CoQ10 --33% reduction in PSA with 100mg in Safarinejedat et al. (2013), 
• "fish oil" and here mostly EPA -- 30% reduction in PSA with 1.2g per day; Safarinejedat. 2013) 
• melatonin (Srinivasan. 2011)
• coffee and coffee polyphenols -- 47% total risk reduction in a recent study by Li et al. (2003); effect was particularly evident in overweight and obese subjects, etc.

but, none of these supplements is a "game changer", let alone able to revert prostate cancer on its own. All that shiny in-vitro data scientists have accumulated for many of the supplements on the above list (and tons of others!) is of little use, as the agents such as resveratrol or curcumin are not going to make it in anywhere similar "petri dish like" concentrations into your blood and right to the tumor to exert their anti-cancerous magic where they are supposed to do it (this is also true for all OTC variants of "enhanced bioavailability" curcumin)... but does that render them useless?

Follow the "Three Simple Rules of Sensible supplementation" (read more)

No, much to the contrary. Most of these "anti-cancer supplements" are either part of the aforementioned diet, already  (e.g. fish, DIM, green tea, ginger, garlic, pomegrenate, tomotoes, watermelon, etc.), or can be part of what Schmitz-Dräger et al. call a "complex diet", when they refer to the overdue "change of paradigm" from single compounds to more complex diets that must be the "starting point of future epdidemiological research" in prostate cancer prevention (Schmitz-Dräger. 2012) - food first, supplements second - and if you chose to supplement, don't lose sight of the "Three Simple Rules of Reasonable Supplementation"

Exercise: Obligatory not facultative!

Contrary supplements, exercise is an obligatory part of the "anti-cancer" lifestyle, of which you should by now realize that it is above all a lifestyle in the most sense. It's not an intervention, a regimen, medication or pill and exercise, in the broadest sense of the word, has to be an integral part and not a doctor prescribed addition to your daily routine. It's not a short term intervention or a quick fix solution and you cannot expect "immediate results". If you start out working out regularly (I suggest to go for at least three and no more than 5 workouts per week), you will be able to reap the fruits of your labor in 10-15 years, when the doctor will stick his finger in your anus and say: "Everything all right Mr Physical Culturist! Absolutely no reason to be worried" (a high fitness level translates to a -64% risk reduction; cf. Olivera. 1996).

You don't want to forget that both exercise and intermittent or alternate day fasting (Varaday. 2008) can help balance the mTOR/AMPK seesaw (read more), and reduce the potential overexpression and overabundance of total and free IGF 1.

Ah, and by the way... whether endurance or resistance training are "optimal" to promote general health and longevity is not a question, simply because both are obligatory. The resistance training to build and maintain muscle mass and the "cardio" training to build (HIIT or HIT) and maintain (LISS) an overall high VO2Max and mitochondrial capacity. That does not mean that you have to run on the treadmill for hours three times a week. But it also precludes going to the gym to sit around "resting" 90% for a "sit your ass flat on the bench and talk with the bros" workout. The latter won't yield a significant glycogen depletion, won't expend significant amounts of energy (-63% risk reduction for 1,000-2,000 kcal being burned during workouts per week; Olivera. 1996), won't increase AMPK (learn more about the "AMPK-mTOR Seesaw"), won't promote autphagy (self-destruction of the cell), won't reduce potentially exuberant IGF-1 levels and won't have beneficial effects on prostate cancer risk.

Don't be scared of your own hormones!

If you pair that with adequate sleep (at least 7h) and light exposure patterns that are both synchronized to your circadian rhythm, there is no reason to be worried about androgens as their effect on prostate cancer is facilitative, not causative (Gershman. 2013), so that even testosterone replacement therapy (TRT) should not pose a problem (Isbarn. 2009).

"Although no controlled studies have been performed to date to document the safety of testosterone therapy in men with prostate cancer, the limited available evidence suggests that such treatment may not pose an undue risk of prostate cancer recurrence or progression" (Morgentaler. 2013)

In fact, case reports and small scale observational studies from Morgentaler et al. and Rhoden et al. clearly suggest that prescribing TRT is not just save even for patients who have just undergone treatment for PCa, it is even more or less warranted, to "reverting iatrogenic hypogonadism and its associated cardiac and metabolic complications" (Aversa. 2012) and can lead to decreases in PSA even in untreated PCa patients (Morgentaler. 2009)

Does estrogen make women better endurance athletes because it increases mitochondrial biogenesis and gears your metabolism towards fatty acid not glucose oxidation? And if that is the case, would men benefit from some more estrogen, as well? Also, what about muscle building, is estrogen your friend or the foe people want it to be (read more)?

Estrogen therapy for prostate cancer? I guess some of you may have thought I was kiddin' when I mentioned that over here in Europe some MDs prefer using synthetic estrogens instead of anti-androgens as a treatment strategy for prostate cancer. As Carl rightly pointed out, this will likewise shut down the production of testosterone and could prevent many of the unwanted side effects on bone and brain. In view of the fact that the progression from benign to highly malignant prostate cancer is usually accompanied by a loss of estrogen beta receptors on the cells (Gabal. 2007), it may yet even serve a more direct purpose, at least in those cancer cells that are still responsive to the estrogen, where the activation of the E2-beta receptor has been associated with a blockade of cancer progression (Hartman. 2012).

Much related to these results is the increasing interest in the usefulness and superiority of intermittent androgen deprivation therapy as an effective alternative to the classic "eradication regimen" with significantly reduced side effects that may yet not be suitable for all patients (Klotz. 2013).

Can your masturbate your way to a healthier prostate?

Apropos side effect. The total eradication of your libido is unfortunately one of the most common side effects of androgen deprivation therapy - I wonder if that happens to the same extent if it's done with estrogen, but I am digressing, ... so back to the libido thing and Carl's absolute favorite, the protective effects of regular ejaculations: 4-7, to be precise is what a  2004 study by Leitzmann et al. found to be associated with a -11% risk reduction in young and a whopping -51% risk reduction in older men (Leitzmann. 2004). We do yet have to be careful, because

1. We all know (at least I hope so) that two parameters that correlate do not necessarily have a causal relationship, as well.
2. The study participants were almost exclusively European Americans and in view of what we have learned from the Hayes study (1999) about the vast differences various dietary factors have on African vs. European Americans, it is not impossible that ejaculations are like grains: beneficial for fair skinned, but carcinogenic for people with dark skin (again no causation implied ;-)
3. We could be dealing with another case of reverse causation, where early symptoms of prostate cancer (like prostate enlargement) cause pain and will have the subjects reduce their ejaculation frequency; luckily the scientists were smart enough to come up with this possible confounding factor as well:
   

   

   A hefty dose of Tongkat Ali is probably not turning you into a bodybuilder, but maybe into a sex machine (read more).

   "We were concerned about the possibility that the observed inverse relationships were due to avoidance of ejaculation among men with early symptoms related to prostate cancer. However, diminished ejaculation frequency as a preclinical consequence of prostate cancer would be expected to be more pronounced among men with advanced prostate cancer than among men with organ-confined prostate cancer, a circumstance that was not supported by our data.
   
   In addition, our findings were essentially unaltered when we excluded cases diagnosed in the early years of follow-up. Hence, our results suggest that reverse causation may have accounted for very little, if any of the observed inverse association between high ejaculation frequency and total and organ-confined prostate cancer risk." (Leitzmann. 2004)

   Thus, pain and subsequent avoidance of sexual intercourse or masturbation does apparently not explain the observed differences.
4. False reporting could be an issue, but within the same cohort of health professionals other studies checked for the accuracy of the reports and found them to be "reasonably accurate" (Leitzmann. 2004). With the questionnaires being totally anonymous, it is thus unlikely that someone lied about his ejaculation frequency.
5. The study did not measure ejaculation frequency during puberty, so that the results are "generalizable to white US men aged 46 years or older" (Leitzmann. 2004), only.

Nevertheless, aside from the Dimitropoulo study from 2009, the negative results of which I discussed on the air (listen to the podcast), there are 9 studies that observed similar beneficial associations (yet not all were significant), 3 studies where no associations were found and 7 studies in which the researchers observed a significant or nonsignificant inverse relationship.

Moreover, we are still at a loss as far as the potential reasons for the touted beneficial effects. Often heard hypothesis usually revolve around

• HPV infections are unlikely the reason for the downsides observed in some of the studies. More recent studies could not find any evidence of previous HPV infections in "the average" prostate cancer patient (May. 2008; Groom. 2012)
  alterations of the composition of prostatic fluid, a decrease of the intraprostatic concentration of xenobiotic compounds and chemical carcinogens, which readily accumulate in prostatic fluid, 
• a reduced development of intraluminal prostatic crystalloids, which have been associated with prostate cancer in some, but not all pathology studies and 
• endogenous effects of the seminal plasma on the local immune responsiveness that may diminish intraprostatic immune surveillance against tumor cells. 

Even the psychological relieve and relaxation that comes with an organism has been implicated as a potential underlying mechanism for the benefits, as the epithelial cell division in the prostate is stimulated by the release of growth factors from adjacent stromal cells that are heavily innervated with α1 adrenergic receptors (summarized based on Leitzmann. 2004)

Against that background I decided (probably much to Carl's dismay, to kick the "masturbate regularly" advice from the initial list of the four pillars of prostate cancer prevention, i.e. diet, exercise, sleep and a reasonable amount of sun exposure. As far as sex and masturbation goes, the jury is simply still out there.

---

So, do we either die from prostate cancer or die with prostate cancer? Those of you who have listened to the show know the answer already. Your chance to die from prostate cancer is 0.018% (CDC data from 2012). So unless you are one of the 188 unlucky guys among 1 million male US citizens, I gather that your chance of dying with "prostate cancer" (i.e. any form of abnormal tissue in your prostate) is probably 10,000x higher (estimated based on data from Zare-Mirzaie. 2012) ... and so is the chance neither you or anyone else will ever notice.

References:

• Aversa A, Francomano D, Lenzi A. Cardiometabolic complications after androgen deprivation therapy in a man with prostate cancer: effects of 3 years intermittent testosterone supplementation. Front Endocrinol (Lausanne). 2012;3:17.
• Barnard RJ, Ngo TH, Leung PS, Aronson WJ, Golding LA. A low-fat diet and/or strenuous exercise alters the IGF axis in vivo and reduces prostate tumor cell growth in vitro. Prostate. 2003 Aug 1;56(3):201-6.
• Campbell TJ, Tindall DJ, Figg WD. Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer. Cancer Biol Ther. 2012 Mar;13(5):237-8.
• Dimitropoulou P, Lophatananon A, Easton D, Pocock R, Dearnaley DP, Guy M, Edwards S, O'Brien L, Hall A, Wilkinson R, Eeles R, Muir KR; UK Genetic Prostate Cancer Study Collaborators; British Association of Urological Surgeons Section of Oncology. Sexual activity and prostate cancer risk in men diagnosed at a younger age. BJU Int. 2009 Jan;103(2):178-85.
• Gabal SM, Habib FM, Helmy DO, Ibrahim MF. Expression of estrogen receptor-B ( ER-B ) in bengin and malignant prostatic epithelial cells and its correlation with the clinico-pathological features. J Egypt Natl Canc Inst. 2007 Dec;19(4):239-48.
• Gershman B, Shui IM, Stampfer M, Platz EA, Gann PH, Sesso HL, Dupre N, Giovannucci E, Mucci LA. Prediagnostic Circulating Sex Hormones Are Not Associated with Mortality for Men with Prostate Cancer. Eur Urol. 2013 Jan 11. doi:pii: S0302-2838(13)00006-7.
• Groom HC, Warren AY, Neal DE, Bishop KN. No evidence for infection of UK prostate cancer patients with XMRV, BK virus, Trichomonas vaginalis or human papilloma viruses. PLoS One. 2012;7(3):e34221. doi: 10.1371/journal.pone.0034221. Epub 2012 Mar 28.
• Grossmann M, Wittert G. Androgens, diabetes and prostate cancer. Endocr Relat Cancer. 2012 Sep 5;19(5):F47-62.
• Hartman J, Ström A, Gustafsson JÅ. Current concepts and significance of estrogen receptor β in prostate cancer. Steroids. 2012 Oct;77(12):1262-6.
• Hayes RB, Ziegler RG, Gridley G, Swanson C, Greenberg RS, Swanson GM, Schoenberg JB, Silverman DT, Brown LM, Pottern LM, Liff J, Schwartz AG, Fraumeni JF Jr, Hoover RN. Dietary factors and risks for prostate cancer among blacks and whites in the United States. Cancer Epidemiol Biomarkers Prev. 1999 Jan;8(1):25-34.
• Ilic D, Forbes KM, Hassed C. Lycopene for the prevention of prostate cancer. Cochrane Database Syst Rev. 2011 Nov 9;(11):CD008007.
• Isbarn H, Pinthus JH, Marks LS, Montorsi F, Morales A, Morgentaler A, Schulman C. Testosterone and prostate cancer: revisiting old paradigms. Eur Urol. 2009 Jul;56(1):48-56.
• Klotz L. Intermittent versus continuous androgen deprivation therapy in advanced prostate cancer. Curr Urol Rep. 2013 Jun;14(3):159-67.
• Li Q, Kakizaki M, Sugawara Y, Tomata Y, Watanabe T, Nishino Y, Tsuji I. Coffee consumption and the risk of prostate cancer: the Ohsaki Cohort Study. Br J Cancer. 2013 Jun 11;108(11):2381-9.
• May M, Kalisch R, Hoschke B, Juretzek T, Wagenlehner F, Brookman-Amissah S, Spivak I, Braun KP, Bär W, Helke C. [Detection of papillomavirus DNA in the prostate: a virus with underestimated clinical relevance?]. Urologe A. 2008 Jul;47(7):846-52.
• McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer. 2008 Mar;8(3):205-11.
• Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009 Feb;55(2):310-20.
• Morgentaler A. Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer. J Sex Med. 2009 Feb;6(2):574-7.
• Morgentaler A. Testosterone therapy in men with prostate cancer: scientific and ethical considerations. J Urol. 2013 Jan;189(1 Suppl):S26-33.
• Oliveria SA, Kohl HW 3rd, Trichopoulos D, Blair SN. The association between cardiorespiratory fitness and prostate cancer. Med Sci Sports Exerc. 1996 Jan;28(1):97-104.
• Rhoden EL, Averbeck MA. Testosterone therapy and prostate carcinoma. Curr Urol Rep. 2009 Nov;10(6):453-9.
• Rohan TE, Howe GR, Burch JD, Jain M. Dietary factors and risk of prostate cancer: a case-control study in Ontario, Canada. Cancer Causes Control. 1995 Mar;6(2):145-54.
• Safarinejad MR, Shafiei N, Safarinejad S. Effects of EPA, γ-linolenic acid or coenzyme Q10 on serum prostate-specific antigen levels: a randomised, double-blind trial. Br J Nutr. 2013 Jul;110(1):164-71.
• Schmitz-Dräger BJ, Lümmen G, Bismarck E, Fischer C. Prevention strategies for prostate cancer. Minerva Urol Nefrol. 2012 Dec;64(4):225-31.
• Srinivasan V, Pandi-Perumal SR, Brzezinski A, Bhatnagar KP, Cardinali DP. Melatonin, immune function and cancer. Recent Pat Endocr Metab Immune Drug Discov. 2011 May;5(2):109-23. Review.
• Taksler GB, Cutler DM, Giovannucci E, Smith MR, Keating NL. Ultraviolet index and racial differences in prostate cancer incidence and mortality. Cancer. 2013 Jun 6.
• Torti TC, Matheson GO. Exercise and Prostate Cancer. Sports Medicine. 2004; 34(6):363-369.
• Varady KA, Roohk DJ, McEvoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK. Modified alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice. FASEB J. 2008 Jun;22(6):2090-6.
• Waldert M, Schatzl G, Swietek N, Rom M, Klatte T. Sex hormone-binding globulin is an independent predictor of biochemical recurrence after radical prostatectomy. J Urol. 2012 Sep;188(3):792-7.
• Zare-Mirzaie A, Balvayeh P, Imamhadi MA, Lotfi M. The frequency of latent prostate carcinoma in autopsies of over 50 years old males, the Iranian experience. Med J Islam Repub Iran. 2012 May;26(2):73-7.

Science Round-Up Seconds: NAC Reduces Inflammation, Muscle Injury & Cytokine Expression, but Impairs Anabolic Signaling, Satellite Cell Activity and Recovery

Inflammatory cytokines won't build muscle, but without them your body won't notice that it's time to adapt.

As a SuppVersity student and listener of the SuppVersity Science Round-Up on Super Human Radio, you will be well aware of the fact that "inflammation" is a pretty loosely - or, I should say, lousily - defined and largely misunderstood term. What most people think of, when they hear the word has little to do with our bodies cytokine reponse (which is "inflammation") and is all about oxidative stress, which is one of the triggers of the release of cytokine. This is a process of which you've already learned that it plays a vitally important role in our bodies' ability to appropriately react to the wear and tear each and every of our cells is exposed to day by day, month by month and year by year. In fact, the misunderstood "inflammation" is a vital necessity to avoid the development of cancer. After all, it is the inflammatory response to the presence of degenerate cells that is what kills them before they can start to proliferate an turn into a systemic problem.

In this context, the feared "inflammatory" markers, IL-6 (interleukin 6) and TNF-alpha (tumor necrosis factor alpha) are of paramount importance as they are part of the singaling cascade that will have our bodies' own defenses target and cull the said degenerate cells before they become "immortal" cancer cells.

Inflammation and the adaptive response to exercise - the hormesis hypothesis

Figure 1: Health and longevity as a function of mitochondrial reactive oxygen species (ROS) formation (learn more)

That being said, previous studies in healthy human beings have yielded conflicting results as far as the effect of normal-to-large doses of exogenous anti-oxidants are concerned. According to scientists like Ristow and Schmeisser from the Department of Clinical Nutrition at the German Institute of Human Nutrition in Nuthetal, Germany, the suppression of the natural / normal cytokine response to the wear and tear of exercise will blunt the hormetic (=everything that does not kill you makes you stronger) response of which they believe that it drives the beneficial effects of working out.

Yet, while there are studies that would confirm this notion, the available data is by no means conclusive and a recent close review of the literature reveals that the consumption of "passive" anti-oxidants (e.g. vitamin C, vitamin E & co, i.e. molecules that simply eradicate reactive oxygen species and will thus blunt not regulate the cytokine response) appears to have either no, or detrimental effects in younger, relatively healthy individuals, the majority of the currently available data in older and sick individuals points to benefits of modest anti-oxidant supplementation.

We know that we know too little...

In short, we are still in the limbo as far as the "to use or not to use antioxidant supplements" question is concerned. Against that background I am grateful for every study that may help us solve this "mystery" and further our understanding of when a perfectly healthy and normal physiological response becomes pathologic and whether, when and for whom the use of specific anti-oxidants may be beneficial.

If you want to hear and learn more about the study at hand, the effects of other anti-oxidants and NSAIDs, and have not had the chance to listen live to yesterday's installment of the Science Round-Up on the Super Human Radio Network I suggest you download the show before you go on reading (click here to download).

Now without taking away too much in advance the latest of theses studies, I can already tell you that the actual outcomes of the latest study from the Democritus University of Thrace in Komotini and a couple of other European institutes, could confirm the scientists' hypotheses that the use of NAC [N-acetyl-cysteine; one of the most potent anti-oxidant supplements] during an 8-day eccentric and thus particularly "muscle damaging" exercise intervention would lead to an increase in GSH availability that would [...]

• ameliorate skeletal muscle performance by reducing inflammatory processes and exercise-induced muscle injury 
• attenuate intracellular redox dependent signaling pathways

and does nevertheless raise the question whether this really is something the average, healthy athlete should be looking for.

Figure 2: Allegedly beneficial effects on the irrelevant markers of inflammation, negative effects on what you are training for - the exercise induced increase in muscle protein synthesis (as evidenced by AKT, mTOR) and satellite cell incorporation (as evidenced by MyoD; adapted from Michailidis. 2013)

If you take look at the data I plotted in figure 2 it is quite obvious that the beneficial effects the participants, 10 healthy male volunteers with at least one month of thrice weekly strength training experience who consumed 20 mg NAC/kg per day (spread in three equal doses) dissolved in a 500-mL drink that contained water (375 mL), a sugar-free cordial (125 mL), and a 2-g low-calorie glucose/dextrose powder to improve palatability, experienced, namely ...

• an attenuation of the exercise induced elevation of inflammatory markers of muscle damage (creatine kinase activity, C-reactive protein, proinflammatory cytokines), nuclear factorkB phosphorylation, and 
• an amelioration of the damage-induced strength decrease during the first 2 d of recovery,

were  accompanied by a blunted increase in phosphorylation of protein kinase B, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase, ribosomal protein S6, and mitogenactivated protein kinase p38 (MAPK) 2d and 8days after the workout.

Now, you could well argue that this is simply a result of less damage, right?

Was it mitohormesis that helped Walter Breuning live to the biblical age of 114 (learn more)?

It would at least seem logical that reductions in structural damage and (potentially - this was not accessed) loss of muscle protein in response to the 300 eccentric unilateral repetitions (20 sets, 15 repetitions/set, 30-s rest between sets) of leg extensions at a speed of 30°/s, the participants performed on an Isoforce (TUR Gmbh) isokinetic dynamometer, would entail a recuduction in compensatory protein synthetic response. In other words, with less damage the same amount of protein (re)synthesis that's insufficient to produce gains or at least restore the baseline protein content in the non-supplemented group could  well suffice to do just that in the NAC group.

(Unfortunately?) this is nothing but a neat hypothesis - one that is not supported by the results of the study at hand, in which the scientists also observed

• a blunted increase in myogenic (=satellite cell replenishing / recruiting and muscle repairing and building) factors and
• the failure to fully recover from eccentric exercise

in the supplement group. It goes without saying that the opposite should have been the case, if our neat hypothesis in defense of NAC supplementation as a means to increase athletic performance and muscle gains by buffering the exercise induced muscle damage, were true.

It's only logical that you wouldn't want to suppress the reactive oxygen species (green-yellow) too much, as their presence in the vicinity of muscle cells (blue) is not just a "stressor", but also important signal that will trigger and regulate the adaptive response to exercise (learn more)

Bottom line: NAC turns out to be an excellent example that well-meant interventions with outcomes that have classically been associated with positive health / performance effects (reduced CK, increased GSH, etc.) do not necessarily translate into beneficial real-world effects. In fact, the long(er)-term consequences of the attenuated cytokine (I am deliberately not using the term "inflammatory", here) response to exercise will probably be rather detrimental than beneficial for the more experienced healthy (young) physical culturist.

For other individuals which have to re-establish a healthy baseline level of glutathione and cut back on non-exercise induced oxidative damage (elderly, obese, diabetics, etc.), it may yet well be the other way around. These people may only be able to benefit from the exercise-induced cytokine response, if it is not drowned by an over-abundant amount of "pro-inflammatory" cytokines from other stressors.

References:

• Michailidis Y, Karagounis LG, Terzis G, Jamurtas AZ, Spengos K, Tsoukas D, Chatzinikolaou A, Mandalidis D, Stefanetti RJ, Papassotiriou I, Athanasopoulos S, Hawley JA, Russell AP, Fatouros IG. Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise. Am J Clin Nutr. 2013 May 29.

Science Round-Up Seconds: The Pro-Insulinogenic Effect of Artificial Sweeteners + Mechanisms & Consequences

Would having your coffee with splenda instead of sugar make this cookie even more hazardous for your glucose metabolism and what about your waistline?

If you've listened to yesterday's installment of the science Round-Up your are probably already in the know of the most important facts about the "pro-insulinogenic" effects of sucralose and how it is (a) neither sure what exactly is causing this increase in post-prandial insulin release, nor (b) whether this is the "bad thing" conventional wisdom would dictate it is.

If you've also read the corresponding press release from the Washington University in St. Louis, I've linked in yesterday's Facebook post on the matter, you will know that even the authors of the study are not yet sure about the real world implications of their results:

"The elevated insulin response could be a good thing, she pointed out, because it shows the person is able to make enough insulin to deal with spiking glucose levels. But it also might be bad because when people routinely secrete more insulin, they can become resistant to its effects, a path that leads to type 2 diabetes."

Before we are getting to those, let's briefly recap what exactly it was, the researchers did and what they observed: M. Yanina Pepino and her colleagues from the Washington University School of Medicine in St. Louis had recruited a group of people belonging to the rare species of obese subjects (BMI 42.3 ± 1.6 kg/m²) who (a) did not use non-nutritive sweeteners and were insulin sensitive. The subjects underwent  a 5-h modified oral glucose tolerance test on two separate occasions which was preceded by consuming either sucralose (experimental condition) or water (control condition) 10 min before the glucose load in a randomized crossover design in the course of which the researchers observed:

• 

  Figure 1: AUC (normalized for mean) and peak values of measured parameters of glucose metabolism (Pepino. 2013)

  20 ± 8% greater incremental increase in insulin area under the curve (AUC) (P < 0.03),
• 22 ± 7% greater peak insulin secretion rate (P < 0.02), 
• 7 ± 4% decrease in insulin clearance (P = 0.04), 
• 23 ± 20% decrease in the calculated insulin sensitivity

• all this occurred in the presence of a faster increase in blood glucose (remember this, it's going to be important)

• aside from the increase in the incremental area under the curve (AUC) for insulin, there were no statistical differences between the AUC (=totally produced) measured serum markers for any of the parameters in figure 2 (top)

Almost as interesting as the things, the researchers did observe were yet changes they didn't observe, namely differences between conditions in active glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, glucagon incremental AUC, or indices of the sensitivity of the β-cell response to glucose. Why this is important? Well, actually you would expect increased GLP-1 and GIP levels, lowered glucagon (the hormone that will have your liver produce glucose) and an increased sensitivity of the b-cells to glucose (why else would there be more insulin floating around), but none of these effects was observed.

So what's the mechanism here, then?

Just like the scientists themselves state: "Although we found that sucralose affects the glucose and insulin response to glucose ingestion, we don’t know the mechanism responsible." (Pepino in an interview with the press guy from the University) and we don't know if these effects of sucralose / splenda are obesity specific or will occur only transiently and disappear upon continuous exposure.

As I mentioned on the show, there are yet a couple of possible mechanisms, all of which are in some form or another related to the sweet taste receptors, which are activated by all natural and artificial sweeteners and are expressed on our tongues, in our intestines and on the pancreas:

• 

  Figure 2: Illustration of the signaling cascade that's initiated by the activation or the sweet taste receptor (based on Lindemann. 2001)

  in vitro studies have already shown a C-AMP (regular) dependent increase in insulin release from pancreatic cells by sucralose (Nagakava. 2009); this was yet not observed in previous human studies, where mostly lean subjects ingested pure sucralose
• the sweet taste receptor appears to have either a heterodimer structure or two distinct incarnations (as shown in the illustration to the right; see figure 2), of which sucralose could trigger only the 2nd pathway which may be insufficient to cause the depolarization of the pancreatic cells to trigger the consequent release of insulin, but it may well suffice to increase the depolarization and insulin release from the pancreas

From another artificial sweetener, namely Acesulfam-K we know that it can also increase the influx of glucose across the intestinal border by increasing GLUT-2 receptor expression (Zheng. 2013), so that this would a third - indirect effect on the insulin response that cannot be totally discarded.

In fact, the upregulation of intestinal glucose transport is the most likely explanation

If we take another look at the study outcomes, it is obvious that this increase in the transport of glucose across the intestinal border would in fact be the most likely mechanism to cause the (in this case appropriate) increase insulin response (more on that in the chapter on whether this is a good or bad thing). Previous studies in rodents also suggest that aside from the acute increase in GLUT-2 receptor expression, the chronic use of artificial sweetener has the ability to upregulate the expression of the "regular" Na-dependent glucose transporter and will thus have a persistent negative effect on what you could call the GI of everything you eat. Accordingly, the scientists speculate

"[...] that regular users of NNS [non-nutritive sweeteners] would have a higher glycemic response after an oral glucose tolerance test on the control day than irregular users and that the acute effects of sucralose intake would be blunted because differences between water and sucralose conditions would be smaller in regular than in irregular users of NNS." (Pepino. 2013)

In other words, chronic users won't be experiencing the effects that were observed in the study, but they will necessarily have a slightly increased insulin response to everything they eat (as long as they are healthy and not yet insulin resistance) irrespective of whether they consume it with or without non-nutritive (not just artificial) sweeteners.

Table 1: Sweetness, dose to stimulate the sweet taste receptor (EC50; based on Matsuda. 2011) and correlation of sweetness and EC-50 value.

In this context, it's certainly worth mentioning that it is unlikely that these effects are sucrolose specific. What is possible, though, is that different artificial sweeteners have more or less pronounced effects. From a 2011 study by Matsuda et al. we know that this is the case for their stimulatory effect on the sweet taste receptor and as my own juxtaposition + calulation of the correlation, which is missing a "minus" sign, in table 1 goes to show you, the "sweetness" measured in units of sucrose (normal sugar) is a relative reliable predictor of the degree to which the different artificial sweeteners activate the sweet taste receptor (not really surprising, is it?)

Being ~300x sweeter than sucrose stevia would by the way be somewhere between acesulfame K and saccharin Na and there is no reason to assume it would not have the same effects, only because it is "natural". I fact the observation Anton et al. made in a 2010 study, where the preingestion of stevia yielded a greater initial glucose spike and a correspondingly higher increase in 30min post-prandial insulin levels than aspartame (~37%) (Anton. 2010). These results clearly suggest that stevia is probably no exception to the rule (it could yet also be that aspartame is an exception to the rule, cf.  "Aspartame's Anti-Insulinogenic Effects During a Workout"; read more) - unfortunately the differences in the study design don't allow for a direct comparison of the Anton and the Pepino study.

And how bad is that?

If we don't really know what the mechanism is and who will be affected to which degree, do we at least know how bad the observed changes are? Unfortunately, the answer is "No", but the notion that any increase in insulin would be bad for you is clearly flawed.

As I hinted at in the show, one of the characteristic feature that renders Pima Indians susceptible to diabetes is the absence of an appropriate early spike in insulin (Lillioja. 1991). Corresponding evidence from other ethnicities (e.g. Kosaka.1996) confirms that the absence of this initial spike (early insulin response) is actually the first step people take on the "Royal Road to Diabesity", the underlying reasons are:

• a failure of immediate suppression of hepatic glucose production, when exogenous glucose is available
  

  "[...] the impact on suppression of hepatic glucose production was dramatic, with the liver releasing glucose at a higher rate despite the presence of hyperglycemia and hyperinsulinemia. The alteration was a direct consequence of the specific defect because restoration of first-phase insulin secretion was followed by complete normalization of hepatic glucose production." (Del Prato. 2001)

• the lack of the stimulatory effects of insulin on peripheral glucose uptake (Del Prato. 2003)

If you did not listen to the podcast yet, you are now probably asking yourselves: "Hold on, but does that not set you up to become obese?" The answer would certainly be yes, if you were insulin resistant, would not work out and would follow a hypercaloric diet with tons of carbs and fats.

Figure 3: Effects of insulin on glucose metabolism, glycogen storage (left) and fatty acid synthesis (right), time-resoled data (0, 2, 4, 8, 12h) on glycogen deposition in skeletal muscle in the inset b/w graph; the data (in mg per kg/min) was measured using an euglycemic clamp in the presence of high, but physiological insulin levels (Koopmans. 1998)

If that's not you, the actual effect of insulin on fatty acid synthesis and thus the amount of carbs that is stored as fat will be of a >20x lower magnitude than the effect insulin exerts on the storage of muscle glycogen - if you extrapolate the data from the first 20min of the euglycemic clamp data figure 3 is based on the ratio could be as high as 2,000x (in other words for each 1 unit of glucose being converted to fat, 2,000 units will be shuttled into the muscle).

"That's all bullocks? Insulin is bad *fullstop*"

If the above is what you still believe I may remind you that insulin is the natural solution to the "sugar problem", only when it seizes working trouble ensues. Moroever, I suppose some of you will be supplementing with pro-insulinogenic agents such as:

• 

  Figure 4: Data from 12 normal subjects using 5g or 10g of oral GABA (Cavagnini. 1982)

  arginine

• taurine

• GABA

• whey

• EAAs

• etc.

I guess it would be easy to extend the list of agents that will increase the insulin response and have still been shown to have beneficial effects on diabetes risk and body composition, but I am to lazy to do this now ;-)

"Where's my Splenda I want more Splenda!"

Before you order a 20kg batch of sucralose from China, now, I do yet still want to remind you of the fact that you can also find arguments in favor of the potential detrimental effects this hitherto non-understood +20% increase in insulin response during an OGGT could have:

• We don’t know about long-term consequences. Will the increase remain or will we “depend” on the artificial sweetener to get an adequate insulin spike in the future (remember the study participants were non-users before)? 
• In the same vein, we don't know what the consequences of the increased intestinal glucose absorption in response to chronic use  (if it is actually present in humans) will be.
• Moreover, although previously published studies don't support this, you could develop an even more pronounced sweet tooth and totally mess the self-regulatory mechanism for food intake that is skewed in the "average Westerner", anyways.
• Importantly, the effects are probably different in the obese + insulin intolerant for them the spike in insulin will have little benefits and tons of downsides (the beneficial effect cited above wrt to the glucose disposal in muscle are probably irrelevant), so that exactly those people who are targeted by artificially sweetened foods could see negative effects which may not be present in lean individuals.
• And lastly, the general beneficial effects of insulin on glycogen repletion depend on glycogen depletion! In other words, if you don’t work out you will not benefit to the same degree, simply because there is no place to put the glucose (it should be said that this is a general problem, which is not specific to dietary sweeteners, but "having room" for glycogen to be stored is a major determinant of whether insulin is rather good or rather bad) 

And if all that is not convincing enough, just remind yourself that we do not even know what exactly is going on here.

---

Bottom line: It does therefore not appear to be indicated to change whatever has been working for you in the past. I can guarantee that you are NOT stagnating because you use a sweetened whey protein or BCAA product. The evidence simply is not there or as Renwick et al. put it in their review, there is "no consistent evidence that low-energy sweeteners increase appetite or subsequent food intake, cause insulin release or affect blood pressure in normal subjects." (Renwick. 2010).

Finally, I guess, I don't have to mention this, but still: I will keep you posted on any future research.

References:

• Anton SD, Martin CK, Han H, Coulon S, Cefalu WT, Geiselman P, Williamson DA. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite. 2010 Aug;55(1):37-43.  
• Del Prato S, Tiengo A. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev. 2001 May-Jun;17(3):164-74.  
• Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycaemia. Diabetologia. 2003 Mar;46 Suppl 1:M2-8. 
• Koopmans SJ, Mandarino L, DeFronzo RA. Time course of insulin action on tissue-specific intracellular glucose metabolism in normal rats. Am J Physiol. 1998 Apr;274(4 Pt 1):E642-50.
• Kosaka K, Kuzuya T, Hagura R, Yoshinaga H. Insulin response to oral glucose load is consistently decreased in established non-insulin-dependent diabetes mellitus: the usefulness of decreased early insulin response as a predictor of non-insulin-dependent diabetes mellitus. Diabet Med. 1996 Sep;13(9 Suppl 6):S109-19. 
• Lillioja S, Nyomba BL, Saad MF, Ferraro R, Castillo C, Bennett PH, Bogardus C. Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab. 1991 Oct;73(4):866-76. 
• Masuda K, Koizumi A, Nakajima K, Tanaka T, Abe K, Misaka T, Ishiguro M. Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. PLoS One.
• Nakagawa Y, Nagasawa M, Yamada S, Hara A, Mogami H, Nikolaev VO, Lohse MJ, Shigemura N, Ninomiya Y, Kojima I. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion. PLoS One. 2009;4(4):e5106.
• Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S. Sucralose Affects Glycemic and Hormonal Responses to an Oral Glucose Load. Diabetes Care. 2013 Apr 30.
• Renwick AG, Molinary SV. Sweet-taste receptors, low-energy sweeteners, glucose absorption and insulin release. Br J Nutr. 2010 Nov;104(10):1415-20.
• Zheng Y, Sarr MG. Effect of the artificial sweetener, acesulfame potassium, a sweet taste receptor agonist, on glucose uptake in small intestinal cell lines. J Gastrointest Surg. 2013 Jan;17(1):153-8.

Science Round-Up Seconds: Breast Cancer, GH Induced Insulin Resistance, Stretch + Contraction Increase Molecular Hypertrophy Signals and Probiotics & the Obesity Pandemic

When we are talking about the extinction of endangered species such as the Siberian tiger, we are adopting a perspective that will also help us to understand such things as the pitfalls of probiotic supplementations as a "solution" to the diabesity epidemic

It's Friday the day after the SuppVersity Science Round-Up (download the podcast) and you all know what that means: Right! Time to summarize the stuff that did not make it into the show and provide you with a couple of thoughts, as well as additional information on the topics, Carl Lanore and I did already cover (this does also imply that you have to listen to the show if you want the info on the genetic and non-genetic underpinnings of breast cancer).

If I had to come up with a motto, something that connects the topics in the show and thus obviously also the ones that will be discussed in this article, I guess it would be "ecosystems". I have repeatedly pointed out in the past that I am not a believer in the "back in the good old days everything was better" interpretation of "Paleo". What I do believe in, however, is the notion that exposition entails adaptation.

You can't control the adaptation, but you can control the exposition

Now, these adaptation processes whether they be negative such as the growth of cancerous tissue in the breast or ovaries of a woman like Angelina Jolie are beyond our reach: The environment that triggers them, on the other hand, can be manipulated - whether that's by getting your breasts and ovaries removed to rid yourself of the 50-80% (you heard me right! the "real" chance carriers of a defect BRCA1/2 gene to develop cancer ranges from 50% to 80%, by the age of 70) or - and this is obviously a pretty drastic change of subjects, by emphasizing peak contractions in a semi-stretched position to benefit from the upregulation of the proteins p-Akt, p70S6K, p38 MAPK and ERK 1/2, i.e. the driving forces of protein synthesis, it's always your manipulation of the environment that will bring about "adaptation" (used in the broadest sense).

Figure 1: Graphical summary of the main results, i.e. the stretch initiated activation (+, ++, +++) of the signaling molecules on different conditions with either short, long (at maximal peak contraction) or slightly longer (+25%, but still way from lockout) positions and the corresponding tension on the soleus muscle of the rodents (Van Dyke. 2013)

If I was successful, the above introduction should have set the scene and thus provided an environment for your perspective on things to change / align with mine. I've manipulated the "cognitive environment" that determines or at least influences the way you are about to understand what follows, i.e. the missing side-kick on the recently observed negative effects of growth hormone on insulin sensitivity and glucose uptake in healthy men and the comprehensive discussion of the (imho) misunderstood role of the gut microbiome as both, a trigger and solution to the obesity epidemic.

Can exogenous growth hormone trigger insulin resistance?

Within our new cognitive framework you will probably have transformed the above question as follows, by now: "How does the exogenous administration of growth hormone change the the endocrine environment and why does this entail an adaptive response of which most people would say that it's highly detrimental?" From this "mini-evolutionary perspective", as you may call it, it's surprisingly easy to understand what exactly has happened in a recent study from the University of Aarhus in Denmark (Vestergaard. 2013).

In their effort to probe the hypothesis that there was a connection between ghrelin, growth hormone and the increases in retinol-binding hormone (RBP4, to be specific) that are observed in patients with developing and/or full-blown metabolic syndrome, Vestergaard et al. conducted two studies of which only the second one, which involved nine totally healthy young men in their twenties (23y; BMI 23kg/m²), will - without major qualifications - transfer to you me or other healthy physical culturists.

The men received a course of daily 2mg GH injections while consuming a previously standardized diet containing 50–60 % carbohydrates, <30 % fat, and roughly 10–15 % of protein (in % of total energy intake). Before and after the intervention period, the participants had to report to the lab at fasted and thus optimally prepared for the hyperinsulinemic euglycemic clamp test.

Figure 2: Basal fasting glucose and insulin concentrations, as well as M-value (=marker of insulin resistance) in healthy young men after eight days of placebo and GH administration, respectively (left; p-values over bars); glucose infusion rates (GIR) indicated by during hyperinsulinemia after placebo / GH administration (right, Vestergaard. 2013)

The selected results I plotted in figure 2 are quite unambiguous. As expected there was a huge increase in the IGF-I concentrations in response to the 8-day course of 2mg GH per day.

The 8% increase in fasting plasma glucose and even more so, the doubling of the insulin levels that were required to keep these elevated glucose levels stable, certainly come as a surprise, if you're thinking about it from an broscientifically influenced mechanistic point of view. I mean, doesn't broscience tell us that GH is the good guy that's going to make you lean and ripped?

How come we are seeing a -34% reduction in glucose sensitivity (this is actually what's measured as the so-called "M value" in the euglycemic clamp studies).

Within our previously established cognitive framework, the answer to this question is actually quite straight forward. To get to the bottom of the counter-intuitive effects of GH we just have to think about the "natural" environment that will trigger the release of GH from the somatotropic cells within the lateral wings of the anterior pituitary gland.

Did you know that the normal GH response to hypoglycemia is blunted in the obese and the reduced obese (Ball. 1972)? Without GH to get their blood sugar back up, overweight individuals and formerly obese will thus have to resort exclusively to corticosteroids (cortisol) to regulate their blood sugar levels.

In this context, it's also worth mentioning that insulin induced hypoglycemia is still considered a valid - yet maybe not optimal - in children who are suffering from retarded growth. With the injection of exogenous insulin and the kids becoming hypoglycemic the body should compensate for that by secreting growth hormone. If that's not the case, this is a good indicator of a general malfunction of the pituitary gland.

Hah? Right! Hypoglycemia or borderline hypoglycemia is among the primary triggers of somatotropin aka GH release. Now, think about it - would it make sense that a hormone that's supposed to increase fatty acid oxidation to supply your body with glucose would at the same time increase insulin sensitivity and thus have your muscles suck up all the precious glucose your brain is longing for?

On the contrary, it is only logical that GH - just like it's falsely vilified potent cousin cortisol (yeah, you heard me right, you won't see both at the scene on the same time, because they serve a similar purpose at least wrt to glucose metabolism) - will decrease the insulin sensitivity of your muscles in order not to "waste" the precious glucose which should be scarce once GH goes up.

In the study at hand, the environment in which the high growth hormone levels occur are totally different: Once you plug people to a euglycemic clamp, there is a mismatch between the actual environment, which is normal / high glucose, and the natural (if you will "evolutionary) expected environment for elevated GH levels - and what you see in figure 2 is the inevitable consequence of this mismatch: a significantly lowered glucose sensitivity... quite cool, how a small change in the way we are looking at things allows us to understand phenomena that do initially appear totally inexplicable, right?

Lifestlye changes, not probiotic supplements are the solution to the diabesity epidemic

Now that we have first-hand evidence for the explanatory power of our new perspective let's stick to it and apply it to the false expectations studies such as the recently released investigation into the "anti-obesity" effects of the common gut bug Akkermansia muciniphila in a rodent model of diet-induced obesity (Everard. 2013).

Figure 3: The AM count is reduced in response to the dietary enviroment, the environment - not the lack of bacteria - is the root cause of the negative effects on fasting glucose, fat mass gain and thickness of the intestinal mucus lining all of which can be partly (the latter even fully) restored to normal with supplementation (Everard. 2013)

If we take a look at the data in figure 3 it is undebatable that the provision of exogenous live (this does not work at all with dead bacteria) Akkermansia muciniphila (AM) can significantly reduce the weight and fat gain in the rodents receiving a species inappropriate high fat diet. As the data on the AM content of the gut microbiome of the obese mice on the right hand side of figure 3 reveals this effect is yet a simple result of the restoration of the "original" microbial composition in the intestinal tract of the rodents.

Siberian tigers on corn fields!? Does this really make sense?

Since the term "original" refers only to the amount of the bacteria Dr Antoon Akkermans identified as one of the many bacteria the count of which is decreased / changed in obese rodents (and humans), it is yet not surprising that we are seeing nothing but ameliorative effects.

Glutamine may offer another way to accelerate gut healing and improve amino acid absorption or rather avoid the "abuse" of BCAAs, arginine etc. for other metabolic purposes (learn more)

Within our cognitive framework of "ecosystems" and "adaptations", the chronic administration of living bacteria to counter a specific aspect of the diet induced detrimental effects on the gut microbiome has may be compared to the laughable efforts of biologists to save certain animals from extinction by breeding them in a Zoo and releasing them into an environment, where deforestation, pollution and all the other nasty things, we, the crown of evolution, enjoy about as much as the average Westerner likes to wash down his super-sized fast food menu with a "refreshing" *rofl* 2L XXL pot of coke (drinking plenty is healthy for you, ain't it? ;-), will have them die before their time unable to reproduce in time to contribute to the species' natural survival.

Once you understand that, you will have to realize that you are wasting your time and money on false promises if you don't change the environment, i.e. the way you live and the foods you eat first before you even think of using probiotic supplements as an adjunct to accelerate the normalization process, which should - just like the detoriation - take place irrespective of the supplementation as a mere results of the dietary modulation of your gut microbiome, anyways.

With these insights, I am going to release you into the weekend... and who knows, maybe you'll notice the effects the environment you expose yourselves to in the coming days has all sorts of beneficial or detrimental influences on your physical and mental health. Listening to even more non-science-based Angelina Jolie news on the television and radio, for example, is probably not going to have beneficial effects on your psyche ;-)

References:

• Ball MF, el-Khodary AZ, Canary JJ. Growth hormone response in the thinned obese. J Clin Endocrinol Metab. 1972 Mar;34(3):498-511.
• Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 13.
• Van Dyke JM, Bain JL, Riley DA. Stretch activated signaling is modulated by stretch magnitude and contraction. Muscle Nerve. 2013 Apr 26.
• Vestergaard ET, Krag MB, Poulsen MM, Pedersen SB, Moller N, Jørgensen JOL, Jessen N. Ghrelin and growth hormone induced insulin resistance: no association with retinol-binding protein-4 Endocr Connect EC-13-0019; published ahead of print May 7, 2013, doi:10.1530/EC-13-0019

Science Round-Up Seconds: Does the Paleo Diet Ruin Your Lipid Profile? Plus: Liver Health & Hepatitis - Milk Thistle & Beyond. Libido Boosters & Real PDE-5 Inhibitors. "Fake" Cinnamon, Coumarin, Bloodthinning & Carcinogenic Cereals.

Is the Paleo Diet unhealthy for healthy individuals? A recent thesis would suggest just that. Learn more about and make up your mind based on the last installment of the Science Round-Up and today's Seconds (img informedhealth.com.au)

I hope you did not miss that the SuppVersity Science Round-Up will as of now always be starting early(-ier) at 12PM EST. If so, don't worry, you can still download the show and listen to Carl and me talking about the things you may be missing, the ones you get extra and those you would rather not have in your supplements and foods. Let's take silymarin, for example, as you have learned on the show, not all "liver assist", "liver clense" or "liver health" products are created equal. Most intriguingly, their ability to scavenge free radicals, as measured by the trolox assay, is not singularly dependent on the actual silymarin content, but will - as the data from the study Anthony et al. conducted (Anthony. 2013) - vary largely, depending on where the milk thistle was grown, how it was processed and thus what else, aside from the purportedly active ingredient is in it.

There is more to natural products than a single active ingredient

If you will, the "there is more to it" was a golden thread that ran through the whole show, but before we follow it up to the next topic, I want to provide you at least an excerpt from the actual data Anthony et al. produced.

Table 1: Selected products tested in the study ordered by their anti-oxidant activity in the TROLOX essay; products with highest TROLOX and anti hepatitis C viral activity highlighted in green and violet, respectively (Anthony. 2013)

As you can see my selection of the 45 products, the scientists bought and tested, reflects what you have already heard on the show: The silymarin content varies largely. In essence, the actual silymarin content may yet not even be that important. If you focus solely on their TROLOX equivalents (TROLOX is a vitamin E like antioxidant and it is used to quantify the anti-oxidant activity in a standardized way - more or less like the meter is used to quantify the length of an object or seconds are used as a standard timespans are expressed in).

More about Liv-52: Actually, the Himalaya(R) product is one of the few OTC supplements with not just one, but more than 20 studies to back its hepatoproctective and antioxidant effects. One thing to keep in min about the research is though that it was - despite being mostly published in peer-reviewed journal - in large parts conducted by scientists who work either for or with the company. As I've pointed out previously, this does not mean that the data is flawed, but it puts observations such as the improved glucose uptake (213%) , the 50% reduction in triglyceride content (anti-NAFLD effect), the 790% increase in glutathione, as well as the decreased TNF-α (-51%) and IL-8 (-550%) and concomitant -65% and -69% reductions of lipid oxidation and DNA fragmentation, respectively, Vidyashankar et al. observed in a recent in-vitro study somewhat into perspective (Vidyashankar. 2012).

If you are looking for the most potent among the readily available products in my selection the most potent "liver protectant" would actually be the PED user's first choice Liv-52, which does not even contain silymarin but is based on an undisclosed amount of  capers (Capparis spinosa), wild chicory (Cichorium intybus), arjuna (Terminalia arjuna), negro coffee (Cassia occidentalis), yarrow (Achillea millefolium) and tamarisk (Tamarixgallica). Bio Silymarin by Advanced Beta Glucon Therapy, on the other hand, is a close second with an almost identical TROLOX value (9.4 vs. 9.5 for Liv-52), is based on silymarin; plus, it exerts 77% more pronounced hepatitis C virus (HCV) antiviral activity than the Himalaya product which lists "viral hepatitis" as the #1 indication on the corresponding website.

As far as these anti-HCV effects, which were standardized against the results the scientists observed in cultures that were treated with 100 U/mL interferon-α, are concerned another Source Natural's Silymarin Plus, emerged as the most potent product. With the "plus" signaling the addition of choline, inositol, vitamin C+E, this observation confirms that antioxidant activity and anti-viral activity are two pairs of shoes - even when the active ingredient (silymarin) is the same.

Apropos active ingredient

You are yet by no means at the mercy of milk thistle and silymarin, when you want to protect your liver from harm. Spices like

• Tumeric (curcumin)
• Coriander

• Garlic
• Red chili
• Black pepper

bust also coffee and green tea, and fruits and vegetables such as

• carrots
• ivy guard
• sweet corn
• soy (for the glycine in it)

• grapes
• custard apples
• Indian gooseberries
• pomegrenade
• sea buckthorn

have potent anti-oxidant and antiproliferative activities (Shukla. 2013)

OTC libido boosters - more than just an alternative

Now that we are talking about alternatives, let's get straight to the next one: The "alternative" to viagra, cialis & co. Honestly, I would hope that you will never have to use one of these (I suggest you take a peak at yesterday's post "The '20 / 30 Principle' Sheds 15% Body Fat in 6 Months, Boosts Testosterone & Sexual Performance in Overweight Men. Plus: Six Signs You're Doing Too Much, Already."; read more), but in the unfortunate case you do, you may be surprised how effective the majority of them actually is.

Figure 1: Categorial breakdown of the adulterated majority of the 91 products from the Campbell study (Campbell. 2013)

A brief glance at the data in figure 2 does yet suffice to see that this is not another case of the "nature knows best principle", but simply a consequence of the fact that the majority of these products do contain either sildenafil and/or taldalfil or some sort of molecular cousin ("analogs" in figure 2). Moreover, in 18 out of these products the dosage was >110% of what would be legit on a per serving base for the prescription varieties (I suspect this is 20mg).

Also mentioned in this context: Saw palmetto is a PDE-5 inhibitor (cf. Yang. 2013). Although the evidence is from a rabbit study, it's pretty likely that there will be at least some discernible effects of saw palmetto on PDE-5 activity an iNOS activity in the human corpus cavernosum, as well.

Coumarin: Carcinogenic & blood thinning cereals

Table 2: Coumarin content in mg/100g of the samples from the Wang study

As unfortunate as it may seem, the chance that the cinnamon you consume with pre-packaged food is "real" (=verum) and from the inner bark of Cinnamomum verum are close to zero. Since this is however the only variety, where you can be almost 100% sure that you don't consume blood thinning and pro-carcinogenic coumarin, it does actually not come as a surprise that cinnamon apple sauce or a cinammon roll bought from the local supermarket contain 0.64 and 2.1mg of this agent on a per serving basis.

If you take a closer look at the rest of the data Wang et al. collected for their latest study (Table 2; cf. Wang. 2013), you may be surprised to see that regular bread, generally unsuspicious oats and purportedly healthy granola bars contain coumarin in amounts that will have you easily surpass the daily uptake limit of 0.1 mg/kg body weight, which was established by the European Food Safety Authority (EFSA) right after it became clear that coumarin is a potential carcinogen... *yamyoll*

Nedless to say that the consumption of respective supplements, which are currently heavily marketed as healthy anti-diabesity agents, could do more harm then good, when the producers play it cheap and put the next best "Cinnamomum XY" they can get their hands on into the caps.

Neither viagra nor cinnamon caps are "paleo", yet still...

E. Trexler titled his recently published thesis "Paleolithic Diet is Associated With Unfavorable Changes to Blood Lipids in Healthy Subjects", which would suggest that the paleo diet is similarly unhealthy as the consumption of "fake", coumarin-loaden cinnamon or high amounts of isolated cholorogenic acid (story is discussed in detail in the podcast; cf. Mubarak. 2013).

Figure 2: Lipid profile (left; values expressed in % of reference levels), fitness and body fat level (right) before and after the Paleo + Crossfit interention (calculated based on Traxel. 2013)

If you take a closer look at the abstract and the actual "side effects" (figure 2), the 10-weeks of paleo dieting + CrossFit-based, high-intensity circuit training exercise program had on the body composition and fitness levels, I personally cannot but ask the following question:

 "What is the significance of the elevations in LDL and minor reductions in HDL in a scenario that produces exactly what has just been shown to be at the heart of the 'Obesity Paradox' and lipid values that are still within the ever-narrowing 'normal' or 'optimal' range?"

I'll leave it up to you to answer this question and decide whether it can really be so bad to rid yourself of all modern, processed foods including any form of processed sugar, soft drinks, and coffees, while fueling your life and workout related energy by increasing your consumption of lean meat, fish, eggs, nuts, fruit, and vegetables. Have a nice weekend!

References:

• Anthony K, Subramanya G, Uprichard S, Hammouda F, Saleh M. Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements. Antioxidants. 2013; 2(1):23-36.
• Campbell N, Clark JP, Stecher VJ, Thomas JW, Callanan AC, Donnelly BF, Goldstein I, Kaminetsky JC. Adulteration of Purported Herbal and Natural Sexual Performance Enhancement Dietary Supplements with Synthetic Phosphodiesterase Type 5 Inhibitors. J Sex Med. 2013 May 1. 
• Mubarak A, Hodgson JM, Considine MJ, Croft KD, Matthews VB. Supplementation of a high-fat diet with chlorogenic Acid is associated with insulin resistance and hepatic lipid accumulation in mice. J Agric Food Chem. 2013 May 8;61(18):4371-8. 
• Shukla SK, Kumar V. Bioactive Foods and Supplements for Protection against Liver Disease. In: Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease. Elsevier. 2013. 
• Trexler, E. Paleolithic Diet is Associated With Unfavorable Changes to Blood Lipids in Healthy Subjects Honors Research Thesis. Ohio State Univeristy. May 2013.
• Vidyashankar S, Sharath Kumar LM, Barooah V, Sandeep Varma R, Nandakumar KS, Patki PS. Liv.52 up-regulates cellular antioxidants and increase glucose uptake to circumvent oleic acid induced hepatic steatosis in HepG2 cells. Phytomedicine. 2012 Oct 15;19(13):1156-65.
• Yang S, Chen C, Li Y, Ren Z, Zhang Y, Wu G, Wang H, Hu Z, Yao M. Saw Palmetto Extract Enhances Erectile Responses by Inhibition of Phosphodiesterase 5 Activity and Increase in Inducible Nitric Oxide Synthase Messenger Ribonucleic Acid Expression in Rat and Rabbit Corpus Cavernosum. Urology. 2013 Apr 23. doi:pii: S0090-4295(13)00169-6.

Science Round-Up Seconds: The Macro-Mineral Alphabet & the Potential Health Hazards of Diet-Induced Latent Acidosis

You lose 600x more sodium than magnesium during a workout. The RDA is yet only ~3-4x higher (Montane. 2007).

If you already listened to the podcast of yesterday's installment of the SuppVersity Science Round Up (if you have not already done so, you can dowload the podcast, here), you may have noticed that I confused the minimal potassium (K) to sodium ratio (Na), which is probably ~1:1, and the "original" K:Na ratio in the "paleo diet".

According to Sebastian et al. (2002) the latter is ~8-9:1 in other words: 8-9 mols of potassium per mol of sodium. That's miles apart from the 1:2-3 ratio the average Westerner (the exact ratio varies depending on which study you refer to) uses as a springboard to hypertension ;-)

The (un-)definite mineral synergism/antagonism chart

Another thing you may have noticed with yesterday's show is the fact that the show was pretty "topic centered". My personal feeling is that it has a much better flow this way and that not despite, but because Carl and I did not cover such a broad range of topics. I cherish the hopefully non-futile hope that you feel the same but am obviously open for any constructive criticism from your side

The SuppVersity macro mineral chart provides a general overview of the complex interactions that exist between calcium, phosphorus, magnesium, sodium, chloride, and potassium (compiled based on various sources)

. This, by the way, does also apply to the corresponding installment of the Seconds, of which you will soon realize that it is not a non-related add-on, but will expand, explain and summarize interesting aspects we've covered in the live show (note: from next week on the Science Round-Up will air at 12 PM EST, the same URL as usual).

On that note, let's start with an "expansion" I already promised to deliver towards the end of the show: some information on the synergism and antagonism of the macro minerals. It's a pretty complex matter and the following illustration is based on generalizations. Some of them, like the low-level exception to the antagonism between calcium and magnesium, of which I believe that it is important to know are explicitly mentioned, others are not.

A very good example of the former, i.e. the important second order interactions is the influence sodium has on the antagonism between potassium and magnesium. The latter disappears, when sodium levels are high and magnesium is needed as a sodium antagonist. Similarly, the often-touted antagonism between magnesium and calcium is actually a co-factor relation, where any "antagonism" is only the result of imbalances between the two.

The good, the bad and the ugly: Just a question of the "wrong" perspective

One thing that should actually be obvious, but is often ignored in all the hoopla about the "good" and "bad" guys among the macro-minerals is that "antagonisms" do not contradict the essential nature of all of the electrolytes, which are - antagonistic or not - in the end, all actors in the same metabolic play.

Figure 1: Average ratio of mineral content (new:old) of 20 vegetables and 20 fruit: data based on comparison of  UK Government’s Composition of Foodsdata at two-time points separated by approximately 50 years (Mayer. 1997)

I mean, take calcium and phosphorus as an example, they are both essential for the structural integrity of your bone and the fact that calcium has a reputation of being the "good guy", while phosphorus is the "bad guy" is just a necessary consequence of the overabundance of the latter, i.e. phosphorus from grains, soft drinks, dairy products, meats, fish, seeds, nuts, eggs and due to the change in mineral ratios (cf. figure 1) even most fruits and vegetables in the food chain of Mr. Joe Average, these days.

According to a 2009 paper by Dana Cordell et al. this may well change in the not all too distant future, after all "the quality of remaining phosphate rock is decreasing and production costs are increasing" (Cordell. 2009). With estimates saying that the demand for phosphorus is going to double within the next 40 years, it stands to reason that the decried overabundance of phosphorus, which is, among other things, also responsible for lowering the zinc content of the produce (cf. Peck. 1980) may be partly reversed within the next decades... I mean, we all know that nothing is as "convincing" as with financial interests, right?

The strong ion difference determines your pH levels

What's the difference between macro-minerals and their "little brothers" the trace minerals? Calcium, sodium, potassium, phosphorus, magnesium, chloride and sulfur are macro-minerals because you need them in amounts that are greater than 100mg per day. Of the trace minerals, on the other hand, you need less (in most cases much less) than 100mg per day. That does not mean though that Iron, zinc, copper, chromium, fluoride, manganese, iodine, molybdenum and selenium were less important - it's merely a quantitative distinction.

While it stands to reason that there is a reason, calcium, sodium, magnesium, and potassium are also called "electrolytes", astonishingly few people can actually give an ad hoc explanation why this is the case - and that despite the fact that their lives depend... no, not on the answer, but on the existence and physiological function of electrolytes ;-)

If you have listened closely to your physics teacher, you will yet probably be aware that an "electrolyte" (electro- ~ charge, -lyte ~ carrier) is a positively or negatively charged molecule (ion) and nothing out of the ordinary in nature.

In your body electrolytes are used to establish ionically charged gradients, similar to the gradient that exists between the positive and negative pole of a battery. These gradients are situated on the cell membranes in excitable tissues, such as muscle and verve, where they facilitate or hinder the influx/efflux of other charged particles.

One of these gradients, in fact probably the physiologically most significant one, by the way, is established by positive sodium (Na+) and potassium (K+) ions and their negative counterpart chloride (Cl-) - exactly those electrolytes you've heard about in yesterday's show (remember: whenever you hear "salt" it actually means Na + Cl).

The electrolytes are not the only charged particles ...

From your chemistry lessons, you may remember that there are not just ionic atoms, but also ionic molecules and that the electron configuration of these particles will determine how they bind, interact and react. But I guess, we have had more than enough complicated theory for today, so if you want to know how the anions and how the strong ion difference (SID) is calculated, check out this brief overview over at acid-base.com.

Rather than going into the details of the mechanism, I decided that it would probably of greater value to wrap the Seconds up with a brief overwiev of the downstream effects of a metabolic state, of which Pizzorno, Frassetto and Katzinger point out that it is not necessarily characterized by acedemia, i.e. pH levels below the "magic" (if we were honest, we'd you'd have to write arbitrary, here) cut-off limit of pH 7.35:

High intensity exercise can also lower your blood pH, an effect you can counter with sodium bicarbonate

"Acidosis only becomes acidaemia when compensatory measures to correct it fail. To illustrate the difference between acidosis and acidaemia, take the following example: two processes occurring simultaneously in the same individual, such as a respiratory acidosis combined with a metabolic alkalosis. In this case, if the respiratory trend toward acidosis is greater than the metabolic trend, a pH of less than 7·35 may be reached, and would be considered acidaemia, despite the presence of a metabolic alkalosis. The intensity of each ‘process’ will determine the pH, but the terms themselves (acidosis, alkalosis) do not indicate a certain pH." (Pizzorno. 2009)

In other words, you don't have to suffer from diabetic or otherwise pathogenic "acidosis", to suffer from one of the following ill health-consequences:

• 

  Hip fracture incidence per 100,000 study participants; aggregated data from cohorts from 33 countries (Frassetto. 2001)

  Calcium loss, bone loss, osteoporosis - Unfortunately, this is not only the best-known side effect of "being too acidic", it's also the only one people take seriously. In that, scientists and lay press alike have zoned in on the high intake of animal proteins as the main confounding factor. But despite the fact that the high sulfur content (methionine, cysteine & co) does certainly contribute to the problem, the data in the figure at the right should make it quite clear that the stuff we eat and don't eat with our meats is at least as much to blame for the misery. In view of the fact that
  

  "[...] cereal grains themselves are net acid-producing and alone accounted for 38% of the acid load yielded by the combined net acid-producing food groups in the contemporary diet" (Sebastian. 2002)

  the average (processed) grain addicted US citizen with his/her quasi-non-existent vegetable intake would end up way on the left side of the x-axis of the graph on the right-hand side, even if he ate not a single gram of animal protein - we would just have to relabel the axis to vegetable/acidd forming food intake (including grains!)".
• Increased renal nitrogen excretion and hampered protein synthesis - One of the less known effects of an increased acid/base ratio is an increase in nitrogen excretion that will obviously not simply hamper your gains, but can also set you up to sarcopenia (age-induced muscle loss).
  
  

  

  Correcting a diet-induced low grade metabolic acidosis with K-bicarbonate reduces the nitrogen loss of 750mg - 1000mg per day (per 60kg BW) in post- menopausal women (Frassetto. 1997)

  In the end, the excretion of nitrogen is nothing, but an adaptive mechanism and a consequence of the catabolism of tissue protein. It is, if you will, a basic necessity for your body to rob your muscle and other tissue of glutamine and all other amino acids, that can be convert to glutamine in the liver, from where it is delivered to the kidney where it's used to synthesize ammonia and excrete the potentially toxic acid load. This will obviously mitigate the severity of the acidosis, it does yet also entail a net loss in muscle and organ protein that cannot be compensated for by an increase in acid forming protein in your diet.
  
  As the data in the figure to the right goes to show you this is a process that's regulated on a day to day basis and the relief in nitrogen loss (data in mg/day/60kg) provided by bicarbonate supplementation (days 0-18) is transient and disappears as soon as you return to your regular low-base, high acid diet (days 19-30).
• Impairments of the growth hormone / IGF-1 axes - Brunnger et al. tested in 1997 whether experimental acidosis would have an effect on the growth hormone / IGF-1 axis and observed a "significant decrease in serum IGF-1 concentration without a demonstrable effect on IGF binding protein 3", which points towards an acid induced "primary defect in the growth hormone/IGF-1 axis" that occurs "via an impaired IGF-1 response to circulating growth hormone with consequent diminution of normal negative feedback inhibition of IGF-1 on growth hormone" (Brunger. 1997). Interestingly, Mahlbacher et al. were able to show that the administration of IGF-1 can in turn ameliorate acidosis and thus correct the previously discussed nitrogen wasting (Mahlbacher. 1999).
  
  

  

  Learn more about the effects of GH, IGF1 and it's splice variants MGF & co and their influence on skeletal muscle hypertrophy in the respective part of the Intermittent Thoughts on Building Muscle (go to the overview).

  In fact, potential physiological effects of the acid-induced impairment of the GH / IGF-1 axes had been observed much earlier, already. McSherry et al. for example report in a 1978 article in the Journal of Clinical Investigations that children with short stature and classic renal tubular acidosis developed normally, when they were treated with adequate amounts of alkalizing agents.
  
  That similar negative effects can be observed even in the presence of "low-grade 'tonic' background metabolic acidosis" was confirmed by Frassetto et al. who observed statistically significant increases (+11%) in 24-hour mean growth hormone secretion in post-menopausal women with diet-induced low-grade metabolic acidosis, when their dietary acid load was neutralized with adequate amounts of potassium bicarbonate (Frassetto. 1997).
  
  In a subsequently published study the scientists argue that the concomitantly observed increases in osteocalcin and bone metabolism would confirm the physiological significance of these changes (Frassetto. 2001). The effects on bone add to the well-known beneficial metabolic effects of growth hormone ( and line up with the recently reported association between low growth hormone levels and memory impairments (Wass. 2010).
  
  In view of the bad press GH and IGF1 are getting, it is important to point out that we are talking about a normalization of the GH/IGF-1 axis, here. It is therefore unlikely that the restoration of a normal acid-base balance will have any of the anti-longevity and pro-cancerous (see next bulletin point) effects of growth hormone and IGF-1 you may have read about in the pertinent literature.
• Potential protective / anti-cancer effects - While conclusive scientific evidence for the involvement of low-grade acidemia in the etiology of cancer is still missing, it has long been speculated that the genetic and epigenetic perturbations, which will turn normal cells into cancer cells may be triggered (among other factors) by disturbances in the acid-base equilibrium. As Ian Forrest Robey points out in his 2012 review of the literature, a diet induced
  

  "[a]cid-base disequilibrium has has been shown to modulate molecular activity including adrenal glucocorticoid, insulin growth factor (IGF-1), and adipocyte cytokine signaling, dysregulated cellular metabolism, and osteoclast activation, which may serve as intermediary or downstream effectors of carcinogenesis or tumor promotion." (Robey. 2012)

  If you want to learn more about the "state of the art research" on the potential link between latent dietary acidosis and the development of cancer, I suggest you simply read the free fulltext of the paper on PubMed. 

I guess, now that you've learned about some of the intricacies of adequate mineral intakes and balances, the acid / base balance, nitrogen and bone loss, growth hormone and cancer, and listened to the interactions of sodium blood pressure, blood glucose and insulin on yesterday's show, it's about time to come back to the simple things that work - the bottom line, so to say...

"What was that about the nutrient sufficiency of the vegetarian / vegan diet, you said on the air?" The above figure shows the % of omnivores, vegans and vegetarians who meet the RDAs  for protein and fiber and selected vitamins and minerals (DiMarino. 2013)

Bottom line: A whole foods convenient-"food" free with the right balance of vegetables, protein, and a reasonable amount of complex largely unprocessed carbohydrates, fats and fruits - call it "ancestral" or "paleo", if you will - is going to provide you with all the minerals you need, it will contain them in the right ratios and supply your body with all the co-factors it needs to use them. It will stabilize your pH levels, normalize your growth hormone / IGF-1 axis and is beyond any doubt the most effective way to get and stay in shape, to reduce your cancer risk, ward off diabetes and lead a life that's not simply long, but also worth living.

If you adhere to these simple rules, there is no reason to be worried about "not getting your minerals" and other essential nutrients. After all, this is what distinguishes you from the "average" western omnivore, vegetarian or vegan who fails to meet most of his or her nutrient requirements.

References:

• Brungger M, Hulter HN, Krapf R. Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: new cause of growth hormone in sensitivity in humans. Kidney Int. 1997; 51:216–221
• Cordell D, Drangert J-, White S. The story of phosphorus: Global food security and food for thought. Global Environ Change. 2009;19(2):292-305.  
• DiMarino A. A Comparison Of Vegetarian Diets And The Standard Westernized Diet In Nutrient Adequacy And Weight Status. The Ohio State University. A Thesis Presented in Partial Fulfillment of the Requirements for Graduation with Distinction from the School of Health and Rehabilitation Sciences of The Ohio State University. 2013. 
• Frassetto L, Morris RC, Jr., Sebastian A. Potassium bicarbonate reduces urinary nitrogen excretion in post-menopausal women. J Clin Endocrinol Metab. 1997: 82:254–259.
• Frassetto L, Morris RC Jr, Sellmeyer DE, Todd K, Sebastian A. Diet, evolution and aging--the pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet. Eur J Nutr. 2001 Oct;40(5):200-13.
• Mahlbacher K, Sicuro A, Gerber H, Hulter HN, Krapf R. Growth hormone corrects acidosis-induced renal nitrogen wasting and renal phosphate depletion and attenuates renal magnesium wasting in humans. Metabolism. 1999; 48:763–770
• May RC, Kelly RA, Mitch WE. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. J Clin Invest. 1986. 77:614–621.
• Mayer AM. Historical changes in the mineral content of fruits and vegetables. British Food Journal. 1997; 99(6):207 - 211
• McSherry E, Morris RC, Jr. At tainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. J Clin Invest. 1978; 61:509–527. 
• Montain SJ, Cheuvront SN, Lukaski HC. Sweat mineral-element responses during 7 h of exercise-heat stress. Int J Sport Nutr Exerc Metab. 2007 Dec;17(6):574-82.
• Peck NH, Grunes DL, Welch RM, MacDonald GE. Nutritional Quality of Vegetable Crops as Affected by Phosphorus and Zinc Fertilizers Agron. J. 1980; 72: 528–534.
• Pizzorno J, Frassetto LA, Katzinger J. Diet-induced acidosis: is it real and clinically relevant? Br J Nutr. 2010 Apr;103(8):1185-94.
• Sebastian A, Frassetto LA, Sellmeyer DE, Merriam RL, Morris RC Jr. Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors. Am J Clin Nutr. 2002 Dec;76(6):1308-16.
• Wass JA, Reddy R. Growth hormone and memory. J Endocrinol. 2010 Nov;207(2):125-6.
• Williams B, Layward E, Walls J. Skeletal muscle degradation and nitrogen wasting in rats with chronic metabolic acidosis. Clin Sci. 1991; 80:457–462