Pomegranate for Statin Users, Magnesium for Cancer-Free Colons, Cialis for Diabetic & Healthy Women and Protein Supplementation for 0.81kg More Muscle & 13.5kg More Strength Gains Than Placebo (Data From Meta-Analysis)

As the data in the graphs at the bottom shows, only vigorous physical activity (right), yet not moderate (middle), let alone light physical activity (left) will help kids to stave off the bad visceral body fat, which increases their waist line from year to year. The photo in the background was by the way taken in 1989 on Orchard Beach, in the Bronx. If I remember correctly that's 6 years before the release of Nintendo's first "Game Boy". And yeah, I got one and it really doubled if not tripled my sedentary time!

7 minutes! That's the SuppVersity figure of the week and a number that should actually ring a bell with everyone of you who is following my advice and pays a daily visit to the SuppVersity Facebook Wall. "Seven minutes" that's what scientists from the University of Alberta and their Canadian colleagues believe would be the amount of "vigorous physical activities" our kids should get (Hay. 2012). I am not sure, if those scientists are still youths, but assuming they are not, I wonder if they cannot remember the amount of "vigorous activity" (which was back in the day simply called "play") they themselves or at least their parents or grand parents got, in the days when you still had to physically kick a ball, if you wanted to play soccer with your friends.

I mean, it's already bad enough that today's kids spend 70% of their time with sedentary activity, only 23% with light activity (like walking from the sofa to freezer ;-), 7% with modest and only 0.6% with vigorous physical activity, wouldn't it be wise then, to rather shoot for the stars and work towards a much higher amount of vigorous activity? After all, even Hay's own study shows that only vigorous activity was associated with a reduced waist circumference and lower markers of metabolic disease (see illustration on the right).

Even if the kids don't make it to the moon, but over to the neighbor's basketball hoop or a public playground that would be a major improvement over the 'exhausting' walks from the Playstation to the fridge and back, wouldn't it?

• Pomegranate the better statin? Adding pomegranate phytosterol (β-sitosterol) and polyphenolic antioxidant (punicalagin) to a statin and reduce adipose tissue ROS production by a whopping 73%!  In their most recent paper Mira Rosenblat, Nina Volkova, Michael Aviram report that the administration of Simvastatin (15 μg/ml) to macrophages in the petri dish did only only "modestly decreased macrophage reactive oxygen species (ROS)" (Rosenblat. 2012), the presence of punicalagin (15 or 30 μM) almost 'extinguished the fire' cutting back inflammation dose-dependently by another 61% or 79%.
  
  

  

  As a regular here at the SuppVersity yo will still be aware that Pomegranate does also contain a potent plant version of CLA, called CLnA, no? Well then go back and read the full article!

  Intriguingly, β-sitosterol alone showed had minor pro-oxidant activity, when it was administered to the J774A.1 macrophages cell line the researchers from The Lipid Research Laboratory in Haifa (Israel) were analyzing,
  

  "the combination of simvastatin, β-sitosterol and punicalagin, clearly demonstrated a remarkable 73% reduction in ROS production."

  So what's the use of the statin, then? After all the scientists also found (but rather not mention in their abstract) that the combination of β-sitosterol and punicalagin actually suppressed macrophage cholesterol synthesis as effectively as low dose Simvastin or high dose Pravastatin (Click here to read about pomegranate in the SuppVersity news)
• Organo-Magnesium stops colon cancer in its tracks by inhibiting inflammation, and the findings a group of researchers from the Gifu University Graduate School report in a soon-to-be published paper are not surprising. After all many epidemiological studies studies like Folsom & Hong (2006), for example, have already shown that there is a -23% reduced risk of developing colon cancer for 55-65 year-old Swedish women in the highest vs. lowers quantile of magnesium intake. Earlier this year Wark et al. conducted a randomized trial and meta-analysis of the hitherto published studies and found:
  

  "Our findings support the hypothesis that higher intakes of dietary magnesium are associated with lower risk of colorectal tumors. The consumption of magnesium-rich foods may be a new avenue to explore further in the search for cancer-prevention strategies." (Wark. 2012)

  Tabs or capsules? A 2010 study has the answer to the question which form of supplemental minerals is the best for you. Roswitha Siener and her colleagues from the University of Bonn in Germany found that magnesium oxide from effervescent tablets is better absorbed than from capsules and you can be pretty sure that similar results will be found for other forms of magnesium. My advice would yet be: Save the money and just go for plain magnesium citrate powder.
  The meta analysis yielded 13% lower risk of colorectal adenomas and 12% lower risk of colorectal cancer for every additional 100mg of magnesium per day. This does yet not mean that by eating pounds of magnesium you could render yourself 'cancer proof', but it is good evidence to make sure to get at least the into the 380-500mg range. And if you want to supplement, you really won't need the organ-magnesium Kuno et al. produced by mixing magnesium oxide (0.22 g), citric acid (0.55 g), malic acid (0.55 g), and glycine (0.22 g) - unless you can't tolerate it, cheap magnesium citrate will do just as well.
  
• Taldalafil for insulin resistant and healthy post-menopausal women?! (Murdolo. 2012) A group of European scientists have found that the administration of 10mg of Taldalfil (the notorious PDE-5 inhibitor in Cialis) to both diabetic and healthy controls led to
  
  • an increase in permeability surface area product for glucose , and
  • skeletal muscle interstitial lactate levels r
  The forearm glucose uptake, as well as the arterial lactate levels showed differential responses, while there was a trend for increased glucose uptake in the healthy controls, the latter was absent in the diabetic group. The profound decrease in arterial lactate levels in the diabetic patients, on the other hand, was not present in the healthy controls, whose lactate levels had already been in the normal range (see figure 1).
  
  

  

  Figure 1: Effects of 10mg of Taldalafil on arterial and intramuscular lactate concentration (Murdolo. 2012). The increase in intramuscular glucose oxidation (evidenced by the lactate that is generated during this process) could even be of interest to healthy women (and men?).

  Based on these findings, Guiseppe Murdolo and his colleagues argue that the results would suggest that acute Tadalafil administration can increase the capillary recruitment and nonoxidative glucose metabolism, without having consistent effects on forearm blood flow and regional lipolytic rate. However...
  

  "[...] notwithstanding the lack of measurable changes on forearm glucose uptake, the microvascular response to tadalafil emerged as an independent predictor of muscle glucose disposal in both T2D patients and insulin-sensitive controls."

  Well, and if those effects don't reach statistical significance, maybe 'others' will. After all a 2003 study by Caruso et al. suggests that Taldalafil can also increase "the frequency of sexual fantasies and of sexual intercourse, and enjoyment" (Caruso. 2003) in a group of  53 pre-menopausal women (age 22–28) years affected by arousal disorders. Maybe we should simply put Taldalfil into the drinking... ah, I am just kidding ;-)
• Finally! Scientists determine 'exactly'*rofl* how much more muscle you can gain with supplemental protein (Cermak. 2012). I hope I do not have to point you towards the irony in the headline of this On Short Notice item. If this ain't your first visit to the SuppVersity you should by now be aware that calculations like add 1g of protein per day and gain x-amounts of lean muscle mass per month, year or whatever timespan are nonsensical and will provide, if anything, a very general orientation.
  
  That said, it is still interesting to see the actual results Naomi M Cermak et al.'s quantitative meta-analysis of 22 studies, of which 77% were conducted with untrained individuals (64% with young trainees) produced. Most studies, which had a duration of 6-24 weeks (median: 12 weeks), used 3-5 x whole body workouts / splits coupled with milk (mostly whey) protein supplementation in amounts that ranged from 10g to 106g - keep that in mind when you think about how 'exact' the following figures can actually be:
  

  • 

    Size-wise and even more so strength-wise Arnold could still benefit from a protein shake after a workout. When it comes to the increases in type I and type II fiber CSA, his age could however put a spoke in his wheel.

    Fat free and fat mass - Compared with the placebo, protein supplementation significantly augmented the gain in FFM during prolonged resistance-type exercise training (weighted mean difference: 0.69 kg). A subgroup analysis for age showed that protein supplementation was beneficial for both the young and the old trainees, but that the total effect size in terms of fat free mass gains were ~1.7x higher in the young subject (+0.81 kg) than in the older ones (+0.48 kg;) subjects.
    
    What I find particularly surprising is that the subgroup analysis also revealed that training status had no significant and what's more, if anything a beneficial effect on the effect sizes in the young untrained (+0.75 kg) and trained subjects (+0.98 kg), respectively.
    
    As far as fat loss is concerned the scientists did not record any statistical significant differences compared to placebo and that despite the fact that the placebo in most of the 22 studies was a sugary carbohydrate drink.
  • Muscle fiber cross sectional area - As the gains in lean mass already suggest, the cross sectional area (CSA) of the muscle fibers increased: By ~ 212µm² in the type I fibers and 291µm² in type II fibers. Unfortunately, both the increases in type I and type II fibers were statistically significant only in the young trainees.
  • 1-RM Strength - The performance for the one-rep maximum (1RM) on the leg press improved across the board (+13.5kg more than in placebo) and that did work almost equally well for younger (+14.4kg) and older trainees (+13.1kg).
  I will leave it up do you what you want to do with this data and whether you think that studies like this are actually useful for the individual practitioner who does not - contrary to way too many dietitians - have to be convinced of the benefits of protein supplementation on top of the low 0.8g per body weight the dietary guidelines recommend.

That's it another saturdaily installment of On Short Notice and in case you feel that you could use some more educative news, tomorrow is another day ;-)

References:

• Caruso S, Intelisano G, Lupo L, Agnello C. Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo-controlled study. BJOG. 2001 Jun;108(6):623-8.
• Cermak NM, Res PT, de Groot LC, Saris WH, van Loon LJ. Protein supplementation augments the adaptive response of skeletal muscle to resistance-type exercise training: a meta-analysis. Am J Clin Nutr. 2012 Nov 7.
• Folsom AR, Hong CP. Magnesium intake and reduced risk of colon cancer in a prospective study of women. Am J Epidemiol. 2006 Feb 1;163(3):232-5.
• Hay J, Maximova K, Durksen A, Carson V, Rinaldi RL, Torrance B, Ball GD, Majumdar SR, Plotnikoff RC, Veugelers P, Boulé NG, Wozny P, McCargar L, Downs S, Lewanczuk R, McGavock J. Physical Activity Intensity and Cardiometabolic Risk in Youth. Arch Pediatr Adolesc Med. 2012 Sep 10:1-8. doi: 10.1001/archpediatrics.2012.1028.
• Kuno T, Hatano Y, Tomita H, Hara A, Hirose Y, Hirata A, Mori H, Terasaki M, Masuda S, Tanaka T. Organo-Magnesium Suppresses Inflammation-Associated Colon Carcinogenesis in Male Crj: CD-1 Mice. Carcinogenesis. 2012 Nov 3.
• Murdolo G, Sjöstrand M, Strindberg L, Lönnroth P, Jansson PA. The Selective Phosphodiesterase-5 Inhibitor Tadalafil Induces Microvascular and Metabolic Effects in Type 2 Diabetic Postmenopausal Females. J Clin Endocrinol Metab. 2012 Nov 1.
• Rosenblat M, Volkova N, Aviram M. Pomegranate phytosterol (β-sitosterol) and polyphenolic antioxidant (punicalagin) addition to statin, significantly protected against macrophage foam cells formation. Atherosclerosis. Available online 31 October 2012.
• Siener R, Jahnen A, Hesse A. Bioavailability of magnesium from different pharmaceutical formulations. Urol Res. 2011 Apr;39(2):123-7.
• Wark PA, Lau R, Norat T, Kampman E. Magnesium intake and colorectal tumor risk: a case-control study and meta-analysis. Am J Clin Nutr. 2012 Sep;96(3):622-31. doi: 10.3945/ajcn.111.030924. Epub 2012 Aug 1.

Science Round-Up Seconds: Are Statins Good for Your Brain? Or Have the Scientists Just Forgotten About the Risks?

Brainy question of the day: Will statins revive or criple your brain?

Those of you who made it in time for yesterday's live-show, will already know that I have "postponed" publishing the (by then) commented list of dietary supplements to improve and maintain insulin sensitivity to Sunday.

It was my original plan to publish this list along with three suggested supplement stacks on Sunday and sticking to it has the advantage of a "true" ending to the "Maintain and Improve Your Insulin Sensitivity" series (read previous posts) - there is already enough chaos among the 1351 published SuppVersity posts ;-).

Furthermore, it will unquestionable be good for your brain, if I do not flood it with an informational overload by trying to cram all the information about the insulin sensitizers, as well ;-)

Download!

Don't forget to download the podcast: If you have not already done so, I suggest you download and listen to the show. With Carl's questions and comments the radio show does also deliver some extra information that is not part of this summary.

I have to admit that I must have over-read the original article a listener who goes by the name "Rad Fox" referenced in an email he send to onair@superhumanradio.com (feel free to bother us with questions for future episodes). In this email "Rad" referenced an article which turned out to be one of these notorious copy + paste pieces of a press release. The latter came from John Hopkins Medicine and discussed the results of an as of now unpublished paper about the incidence of dementia in patients on statin therapy.

This is not the first review that connects statin use to brain health!

Despite their bad reputation within the health and fitness community, the use of statin drugs has in fact been shown in numerous studies to keep your brain on top of the game. Another very recent meta-analysis of data from studies with 2851 cases and 57020 participants, for example, says that statin use is associatied with a statistically significant -48% reduction in dementia risk (Song. 2013). Similarly, Steenland et al. write in a paper that's been published roughly a month ago:

"Research volunteers with normal cognition at baseline evaluated an average 4.1 times over 3.4 years (1,244 statin users, 2,363 nonusers) and with mild cognitive impairment (MCI) at baseline evaluated an average 3.9 times over 2.8 years (763 users, 917 nonusers)." (Steenland. 2013)

Irrespective of the high number of empirical studies that seem to support the efficacy of statins as "anti-dementia" drug, I did not even have to bother with PubMed or any other medical database to find trials that suggest that the use of statin drugs will have the exact opposite effects. I just had to scroll down to the end of the article, where I found a news report on an study that claims that Pravachol, obviously likewise a statin drug, would be "linked to memory impairment" (read the news story).

Beneficial or detrimental? Which results can you trust?

Your body does in fact produce i's own anti-dementia "drug": Melatonin. With the natural decline of the metlatonion production with age, it is thus only logical that you develop dementia, only in your older age - learn how to protect yourself with melatonin

I know it can be enervating at time, but it's one of the central characteristics of science that it's results are usually ambiguous and far from achieving the status of "undebatable truths". If you've been around the SuppVersity for some time now, you should by now have overcome this naive understanding of the nature of science by now, anyways.

"The promising results obtained in vivo and in epidemiological studies are generally not in accordance with those of placebo-controlled randomized clinical trials." (Silva. 2013)

You should also be aware that the best way to reconcile these discrepancies between epidemiological and experimental evidence is to identify the underlying mechanism behind the effects statins exert on the build-up of neuronal plaque. As soon as we know exactly what's happening we may well be able to decide whether the protective effects we see are "real" or just an "epidemiological Fata Morgana".

The most important question we have to answer is: "HOW?"

Unless we have a rationale explanation for the protective effects statins may have on the brain of (elderly!) individuals, we can file the claim "statins protect elderly brains against cognitive decline" in the "still to be investigated" folder and let it rest there until we have a verifiable theory (= sum of hypothesis) to explain how the use of a drug that was originally designed to block the endogenous production of cholesterol could have such an effect on the brain.

Dietary vs. endogenously produced cholesterol: I know that most of you will be aware that statins reduce your bodies own (=endogenous) production of cholesterol. Most of you will probably also know that it is this endogenously produced cholesterol that is - if any form of cholesterol - to be held responsible for coronary heart disease and (purportedly) the formation of plaque in the brain.

If you are not a narrow-minded text-book physician, you will have to acknowledge that eggs promote an anti-artherogenic cholesterol profile and will thus probably have anti-Alzheimer's and anti-dementia effects (learn more)

For the average human being, his dietary cholesterol intake will have no or only minor influence on the serum levels of cholesterol and cholesterol rich foods such as eggs, have actualle been found to exerd positive effects on the cognitive function of elderly individiuals (Aparicio. 2013); and despite the fact that the results did lose their significance, when they were stratified for total energy intake and education level, the Aparicio study should remind us that the role cholesterol rich foods do not necessarily increase your dementia risk, even if cholesterol was mechanistically involved in the etiology of dementia - even if studies in rodents and rabbits who were fed with synthetic high cholesterol diets suggest otherwise (learn more about the problems with synthetic diets).

And what about saturated fat? In a study from Japan (the Hisayama Study; cf. Ozawa. 2013), the consumption of a diet with a normal amount of saturated fat in it and not the allegedly healthier "almost zero SFA" pattern were associated with reductions in all cause (-34%), Alzheimer's (-35%) and vascular dementia (-55%) - a direct negative effect of saturated fats is thus unlikely. A negative impact of certain foods that happen to have a high amount of saturated foods in them, on the other hand, cannot be excluded.

The most straightforward explanation for the beneficial effects scientists observed in numerous epidemiological studies would obviously be a direct one: "Statins take away a substrate that's necessary for the amyloid plaque to form." This hypothesis would also be supported by significant correlations between elevated serum cholesterol levels and plaque build-up in the brain, as they were observed by (among others) by Matzusaki et al. in who used the same cohort Ozawa et al. analyzed in their study on the influence of certain dietary patterns on the risk of developing dementia (see red box above). In the corresponding paper Matzusaki et al. report:

Table 1: Official "normal" levels for total, LDL & HDL cholesterol, as well as triglycerides (based on AHA recommendations)

• 23x higher risk for total cholesterol > 5.8mmol/L
• 13x higher risk for LDL > 4.02 mmol/L
• 70% higher risk for HDL < 1.04 mmol/L (p > .5)
• 3.5x higher risk for triglycerides >1.56mmol/L
  that's compared to Q1 <0.51mmol/L
• 7x higher risk for LDL / HDL > 3.48 mmol/L
• 3.1x higher risk for “non-HDL” > 4.61 mmol/L

What makes Matzusaki et al.'s observation particularly interesting is the fact that they are based on 147 autopsies that were performed between 1998 and 2003. Autopsies? Yes, I know that sounds gross and irrelevant, but it has the advantage of

• being able to measure the amount of plaque directly,
• having physical and quantitative data, and
• not being limited to diagnosed cases of dementia.

In other words: Your data is not going to be skewed by analyzing only those who are already sick enough to be treated, when you are able to look at the brains of a representative sample of the population after they died.

Dead or alive, there is more than one hypothesis

Remember: We are inclined to forget that the only difference between "effects" and "side effects" is our assessment of the latter. The beneficial effects statins have on the expression of AGE receptors, for example would be  "side effects" for a classic statin which is obviously supposed to lower cholesterol and nothing else. In the context of dementia prevention, this side effect it is the intended effect and the cholesterol lowering effects of statins are the "side effects".

In view of the myriad of already discovered and hitherto undiscovered "side effects" of statins it is however just as likely that the reduced dementia risk is a result of  ...

• a reduction in advanced glycation end product receptors in the brain and thus a protection against the negative effects AGEs exert on the brain (Liu. 2012; Deane. 2012).
  On a side note: If you want to counter the production of endogenous AGEs you can do so with taurine (Nandhini. 2004). This would obviously render the use of a statin to reduce the receptor density obsolete.
• a blockade of the “maturation” from plague precursors to amyloid beta plaque (Hosaka. 2013)

... or a combination of all these effects with the direct and indirect role cholesterol plays in the formation of plaque in the brain (Fantini. 2013; Hung. 2013).

Whether we will ever really know that it is that appears to protect statin users from dementia is thus obviously still anybody's guess. What is not "anybody's guess" is whether it makes sense to take a statin solely to protect yourself from developing dementia. That would - in my humble opinion - rather be a sign of existing cognitive decline than a protection against its development ;-)

Bottom line: Despite the fact that I have never been a statin advocate it is difficult to argue with the current epidemiological evidence: People who take statins have a lower incidence of dementi *fullstop* Whether this is even related to cholesterol is however as questionable as Carl's suggestion that it's an overall reduction in inflammation as it has been observed by Reis et al. (2012) in the context of Malaria infections, where statins appear to be able to sooth the "brainflammation" that's behind the beneficial effects of statin drugs.

Those who take statins can benefit from eating pomegranate | learn more

What is more or less undebatable, though, is that "there is insufficient evidence to recommend statins for the treatment of dementia" (McGuinness. 2013). I will leave you with this conclusion from the latest Cochrane review and a discreet reference to the influence of APO-E phenotypes on both baseline cholesterol levels and the development of Alzheimer's disease. Who knows? If we controlled for the APO-E4 allele, we may well find that carriers of the AA (=2x positive) form of the APO-E4 gene, of which a recent study from the University of Toronto suggests that having this homozygous APO-E4 gene poses a 56.0x higher risk (no typo!) of developing dementia (all forms), benefit from taking a statin while others don't? I will obviously keep you posted on all future developments.

References: 

• Aparicio Vizuete A, Robles F, Rodríguez-Rodríguez E, López-Sobaler AM, Ortega RM. Association between food and nutrient intakes and cognitive capacity in a group of institutionalized elderly people. Eur J Nutr. 2010 Aug;49(5):293-300.
• Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ. 2002 Oct 26;325(7370):932-3.
• Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012 Apr 2;122(4):1377-92. 
• Fantini J, Yahi N, Garmy N. Cholesterol accelerates the binding of Alzheimer's β-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation. Front Physiol. 2013;4:120. doi: 10.3389/fphys.2013.00120.
• Liu R, Wu CX, Zhou D, Yang F, Tian S, Zhang L, Zhang TT, Du GH. Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC Med. 2012 Sep 18;10:105. 
• Hosaka A, Araki W, Oda A, Tomidokoro Y, Tamaoka A. Statins reduce amyloid β-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons. Neurochem Res. 2013 Mar;38(3):589-600.
• Hung YH, Bush AI, La Fontaine S. Links between copper and cholesterol in Alzheimer's disease. Front Physiol. 2013;4:111. 
• Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study. Neurology. 2011 Sep 13;77(11):1068-75.
• Nandhini AT, Thirunavukkarasu V, Anuradha CV. Stimulation of glucose utilization and inhibition of protein glycation and AGE products by taurine. Acta Physiol Scand. 2004 Jul;181(3):297-303. 
• Ozawa M, Ninomiya T, Ohara T, Doi Y, Uchida K, Shirota T, Yonemoto K, Kitazono T, Kiyohara Y. Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin Nutr. 2013 May;97(5):1076-82.
• Reis PA, Estato V, da Silva TI, d'Avila JC, Siqueira LD, Assis EF, Bozza PT, Bozza FA, Tibiriça EV, Zimmerman GA, Castro-Faria-Neto HC. Statins decrease neuroinflammation and prevent cognitive impairment after cerebral malaria. PLoS Pathog. 2012 Dec;8(12):e1003099.
• Silva T, Teixeira J, Remião F, Borges F. Alzheimer's disease, cholesterol, and statins: the junctions of important metabolic pathways. Angew Chem Int Ed Engl. 2013 Jan 21;52(4):1110-21.
• Song Y, Nie H, Xu Y, Zhang L, Wu Y. Association of statin use with risk of dementia: A meta-analysis of prospective cohort studies. Geriatr Gerontol Int. 2013 Mar 6.
• Steenland K, Zhao L, Goldstein FC, Levey AI. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc. 2013 Sep;61(9):1449-55.

SuppVersity Science Round-Up: Dairy, Diabetes, Estrogen, IGF-1, Cancer & More + Statins, Fat Gains & Diabesity Risk

Now you tell me there was nothing magic about milk (poster from the CMPB "Got Milk" campaign)

If you actually made it to the end of yesterday's podcast and were not so bored that you fell asleep (specifically during the passage where Carl was praising me to the skies ;-) you will already know that today's summary is above all going to provide you with some figures, suggested reads and, of course, references.

Hey, David! Is there something magic about milk?

I would also like to emphasize that both explanations I presented to explain the absence of beneficial effects of full-fat dairy and the non-significant detrimental effects of full-fat milk, yesterday, are just as the word implies "hypothetical" and I am not claiming to be sure that any of them fully explains the high vs. low fat difference. To be honest, I would be flabbergast if only one of them was the - meaning the only - reason that full-fat milk consumption does not yield the same reductions in diabetes risk as skim or low fat milk (and dairy in general).

Even the common notion that a high omega-6 to omega-3 ratio could be the culprit (hypothesis II, in yesterday's show), is by no means non-debatable; and that despite the fact that the current vilification of omega-6 fatty acids as yet another "root of all nutritional evil" would suggest so:

• A 2012 study from the Uppsala University, for example, found in a one-to-one comparison of a high linoleic acid (omega-6) vs. saturated fat (SFA) diet that those of the 61 abdominally obese subjects (15% had type 2 diabetes) who had been assigned to the diet that was high in vegetable n−6 PUFA instead of the SFA diet (butter), had much better fasting insulin levels (64.2pmol/L vs. 79.0 pmol/L), recorded a small but significant positive effect on the visceral / subcutaneous adipose tissue ratio and even reduced their body fat percentage minimally (-0.1% vs- +0.6% in the "buttered" group; cf. Bjermo. 2012). Surprising if you stick to the mainstream all-across the board condemnation of cones (baked-on sunflower oil), margarine, sunflower oil, and sunflower seeds, which were the main dietary PUFA sources in the high PUFA group, isn't it?
• On the other hand, mechanistic insights into the underlying cause of the detrimental effects of the saturated fat can be found, among others, in Lee et al. (2006) who report that the diaglycerol build-up (DAG) in skeletal muscle that occurs when you feed rodents a high saturated fat diet is responsible for the subsequent development of insulin resistance that was observed by Bjermo et al. in their previously cited human study (Lee. 2006)

This means, it may well be that it's not the "bad omega-6 content" that's to blame (remember: the evidence for an omega-6 <> diabetes connection is really weak; things look different wrt to CVD, though), but rather the very same saturated fat that has long been falsely held solitarily responsible for "all things bad" wrt to fat.

Here is a simply truth: Your milk contains, what your dairy cows eat

With the emerging evidence on the overall health benefits of a low(er) n6:n3 ratio it is still important to be aware that the n-6:n-3 ratios do vary significantly even for those cows that would be considered "pasture fed" depending on the actual amount of pasture in their feed (5:1 for 1/3 pasture, 1.9:1 for 2/3 pasture and 0.7:1 for all pasture; cf. Dhiman. 1999; figure 2, left).

Figure 1: Milk fatty acid composition depending on amount of pasture in the diet (left, Dhiman. 1999); n-6:n-3 ratio of milk from alpine cows depending on the feed they received (right; Leiber. 2005)

Moreover, even with the "worst" milk from 100% soy-fed animals (data not shown, but explicitly mentioned on the show; cf. Mansbridge. 1997), we do see a lower n-6:n-3 ratio than in the current American diet (~7:1 vs. 15:1-17:1 for the US diet, cf. Simopoulos. 2002). Drinking milk would thus actually improve the average American's n6:n3 ratio compared to "the average fatty food" - in particular if he / she would get it from grass-fed "low performance" (=low milk yield) cows as the ones in Leiber et al.'s study on the fatty acid composition of milk from Alpine origin (Leiber. 2005).

So if it's not the omega-6 content reduces the value of full-fat milk?

Obviously, these insights leave us with the question what else it may be that links regular full-fat milk and diabetes. Also: Why is this link not significant? In the end, it could simply be adding full-fat milk on a diet that already has plenty of fat and sugar in it that's the problem - not all people who consume high amounts of milk would yet fall into this category so that you would see those with an otherwise spot on diet benefit, while those on the standard American diet are doing more harm than good. If we also consider the real-world bias due to the bad rep of full-fat and good reputation of skim or low fat dairy, it should be obvious that your average low fat dairy eater is more likely to watch his diet than his high fat dairy loving neighbor. Together this could certainly explain why the results suggest a statistically non-significant 12% risk increase per 200g of full-fat dairy per day - the gap between those who benefit and those harm themselves is simply too wide to achieve statistical significance.

Figure 2: Changes in diabetes risk for 400/day (all dairy) and 200g/day (all other items listed) increase in intake, data based on meta-analysis of 17 cohort studies (18 publications); of which seven were from the US, six from Europe, two from Asia and two from Australia (Aune. 2013)

Another thing that could explain this gap is albeit the homogenization hypothesis (read my previous elaboration in "Mutant Milk" | read more). You could for example argue that you will either consume homogenized or non-homogenized full-fat milk, but won't jump back and forth between the two because one (the homogenized milk) does not even taste like milk (and this is not just my opinion ;-) - if the homogenization hypothesis which does not necessarily say that homogenization is bad, but that it will reduce the beneficial effects of the larger sized lipids (cf. Oosting. 2013; learn more) that are broken down when the milk is forced at high pressures through a <1 µm sieve.

What about estrogens in milk?

And what about cancer? The evidence that milk induces cancer is at best weak (Chagas. 2012). Even from a mechanistic point of view, dairy can only promote cancerous growth by its general growth promoting effects (those are exerted via the IGF, mTOR, Akt pathway, by the way;  the same pathway that makes your muscles grow, as well). Moreover, there is evidence that dairy reduces the incidence of cancer in the digestive tract (-16% in men; -23% in women; cf. Park. 2009); and as far as prostate and breast cancer risk is concerned, there is significant evidence almost exclusively for high fat milk and (when measured) always in the presence of evaluated IGF-1 levels.

So, the bottom line here is simple: A high dairy consumption within a high energy diet + chronic inflammation context will certainly boost cancer growth more than a generally growth-retarding vegan diet - that's for sure! This does yet not mean that "dairy causes cancer".

While a recent follow-up of the Nurses' Health Study (yeah, yet another one; and, yes! I am fed up with it, too) claims that the already minimal association of dairy consumption with a later transition into menopause (~3months on average) could be to the "hormonally active nature" (Carwile. 2013) of milk, it is pretty certain that this is not a result of it's estradiol content, because...

1. ...the effect was observed only for low fat dairy and low fat milk, which has a much lower estradiol content than the full-fat varieties that did not postpone the onset of menopause
2. ...even the highest estrogen (and highest fat, by the way) common dairy product, namely butter, has an E2 content of "only" 82pg/g (Wolford. 1979), so assuming you were eating a whole 250g packet of butter everyday you would get a pretty whopping amount of 20,500pg of E2 from it, but even if you extracted that and injected it right into your bloodstream you would end up with "only" ~4.1pg/ml in your blood and that's way below the lower limit for men which is 14pg/ml and almost 100x below the preovulatory peak value in women.

Needless to say that the loss in the gastrointestinal tract and the natural clearance in your liver reduces the oral bioavailability to almost zero. There is a good reason that oral hormone preparations are usually methylated or use other techniques to duck the first path metabolism and clearance in / by the liver (Fotherby. 1997).

So, if milk does have any "hormonal" side effects those are probably mediated, but not necessarily caused by it's indirect effect on IGF-1 production (see box on the right).

---

Everything in moderation and statins only when they are really necessary: Before I wrap things, up I want to briefly mention the active ingredients of the pro-obesogenic statins, which are Rosuvastatin (Crestor; causes NAFLD, as well), Atorvastatin (Lipitor), Fluvastatin (Lescol, Canef, Vastin), Lovastatin (remember: we are talking about subcutaneous fat which is rarely measured in pertaining studies and may thus hitherto been overlooked). And let's not forget an "honorable mention": Simvastatin (Vitoryn & Inegy) was the only statin in the study from the University of Pais Vasco (Aguirre. 2013) that did not lead to a further deterioration of the already compromised insulin sensitivity of the obese rodents.

And what about humans? The increase in diabetes risk is real. Not just in rodents. The increased diabetes risk due to statin treatment Satar et al. calculated in their 2010 meta analysis of 13 trials with more than 90,000 subjects is ~9%. If you want to learn more about the study, click here to watch a video interview with Prof. Satar. He also elaborates why patients at high risk of heart disease (which is not everyone with high cholesterol) can still benefit from statin treatment and how muscular side effects and effects on the liver could be the underyling cause of the increase in diabetes risk he and his colleagues observed.

Suggested read: "Ask Dr. Andro: Are Colostrum and Milk Products in General Healthy Muscle Builders, a Waste of Money or Toxic Waste?" | read more

The latter is obviously still no reason to pop Simvastatin as if it was candy. While there is good evidence that people with high cholesterol and a messed up lipoprotein profile (many small vs. few large and fluffy cholesterol molecules, as well as high LDL/HDL and high TRIG/HDL levels, learn more) benefit from statins. Being above the arbitrary cut-off limit for total cholesterol is imho not enough to qualify as "in need of statin treatment" potentially see more benefits than downsides of taking statins.

In a very similar vein, consuming a gallon of low fat dairy is NOT going to reduce your diabetes risk to zero (although basic math may suggest that) - everything in moderation, folks ;-)

References:

• Aguirre L, Hijona E, Macarulla MT, Gracia A, Larrechi I, Bujanda L, Hijona L, Portillo MP. Several statins increase body and liver fat accumulation in a model of metabolic syndrome. J Physiol Pharmacol. 2013 Jun;64(3):281-8.
• Aune D, Norat T, Romundstad P, Vatten LJ. Dairy products and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. Am J Clin Nutr. 2013 Aug 14. [Epub ahead of print]
• Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, Berglund J, Pulkki K, Basu S, Uusitupa M, Rudling M, Arner P, Cederholm T, Ahlström H, Risérus U. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr. 2012 May;95(5):1003-12.
• Carwile JL, Willett WC, Michels KB. Consumption of Low-Fat Dairy Products May Delay Natural Menopause. J Nutr. 2013 Aug 14. [Epub ahead of print]
• Chagas CE, Rogero MM, Martini LA. Evaluating the links between intake of milk/dairy products and cancer. Nutr Rev. 2012 May;70(5):294-300.
• Dhiman TR, Anand GR, Satter LD, Pariza MW. Conjugated linoleic acid content of milk from cows fed different diets. J Dairy Sci. 1999 Oct;82(10):2146-56. 
• Fotherby K. Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy. Contraception. 1996 Aug;54(2):59-69. Review.
• Lee JS, Pinnamaneni SK, Eo SJ, Cho IH, Pyo JH, Kim CK, Sinclair AJ, Febbraio MA, Watt MJ. Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites. J Appl Physiol. 2006 May;100(5):1467-74. 
• Leiber F, Kreuzer M, Nigg D, Wettstein HR, Scheeder MR. A study on the causes for the elevated n-3 fatty acids in cows' milk of alpine origin. Lipids. 2005 Feb;40(2):191-202.
• Mansbridge RJ, Blake JS. Nutritional factors affecting the fatty acid composition of bovine milk. Br J Nutr. 1997 Jul;78 Suppl 1:S37-47.
• Oosting A, van Vlies N, Kegler D, Schipper L, Abrahamse-Berkeveld M, Ringler S, Verkade HJ, van der Beek EM. Effect of dietary lipid structure in early postnatal life on mouse adipose tissue development and function in adulthood. Br J Nutr. 2013 Jul 11:1-12. [Epub ahead of print]
• Park Y, Leitzmann MF, Subar AF, Hollenbeck A, Schatzkin A. Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study. Arch Intern Med. 2009;169(4):391-401. 
• Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42.
• Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002 Oct;56(8):365-79.
• Wolford ST, Argoudelis CJ. Measurement of estrogens in cow's milk, human milk, and dairy products. J Dairy Sci. 1979 Sep;62(9):1458-63.

Chest Fat, Bitch Tits, Chesticles, Gynecomastia, Lipomastia and Co.: Infinite Ways to Name it, 45 Ways to Prevent It

Image 1: Luckily "gyno", or in this case lipomastia, does not always look that bad. Oftentimes it is more subtle, yet still annoying a psychological burden for men suffering from it. This pictures alone should be reason enough to give all the 45+ contributing mentioned in this article a wide, wide berth (image from  cosmeticsurgerybangalore.com)

If you type "gynecomastia" into your favorite search engine, your chances to find one of the major fitness and bodybuilding forums among your first hits are about 99%. This indicates that gynecomastia, lipomastia, "bitch tits", "fat tits" and whatever else many people use to measure by the same yardstick is much more prevalent than you would think if you conducted a survey on the street. The reasons for that are manifold. Men, who frequent those bulletin boards are oftentimes more conscious about their looks than Mr. Average, they are also more prone to be exposed to exogenous hormonal agents that can contribute to the development of the aforementioned unaesthetic pathologies. Most importantly, though, gynecomastia is something you don't talk about. You have it, you suffer, but you don't talk publicly about it - after all, that would just make you even more unmanly! Right? No, false! Utterly false!


In fact, the widespread implicit understanding that the above statement was right is a damn good reason for me to do the opposite and talk, or rather write about causes (today's installment) and ways to get rid of this humiliating condition (next installment updated!).

Why does my chest look like that, god damnit?

According to the currently accepted scientific paradigm, gynecomastia is a result of hormonal imbalances; mostly an overabundance of estrogen, which stimulates the glandular tissue of the male breasts and thus contributes to its growth and, in some cases, cancerous degeneration. The underlying reasons for these imbalances, on the other hand, are manifold and only partly understood. And while we will have a closer look at numerous individual factors in the following paragraphs, exogenous estrogens and estrogen like substances, an increased metabolism of androgens and an inhibition of the degradation of estrogens in the liver are probably the worst offenders (if you are interested in male health, I highly recommend, you also last week's article on "Natural Hormone Optimization: 10 Things to Avoid for Optimal Androgen Levels").

"Prolactin gyno" - does it exist? Although I suspect that >60% of the "prolactin gynos" you read about on the pertinent bulletin boards are in fact mediated by high estrogen levels, there is scientific evidence for the occurrence of abnormal tissue growth in patients with prolactin-secreting tumors (Giminez-Roqueplo. 1999) - it thusly appears possible that compounds which either interact directly with the respective receptors or the administration of which will produce abnormally high prolactin levels, could lead to the development of gynecomastia in men. In view of the antagonistic relationship of prolactin and dopamine and the complicated interactions between dopamine and testosterone levels, it is yet well possible that this is just another instance of hypogonadism, in this case as a result of elevated prolactin and suppressed dopamine production.

These imbalance do not inevitably lead to an actual increase in breast tissue, though. Minor imbalances or chronic low exposure to synthetic or natural estrogens / estrogen-like compounds will often produce a general often subtle feminization of the male body, which is accompanied by an increased deposition of body fat in the chest area. In more severe cases, this can be a very pronounced accumulation of dense adipose tissue right under and around the nipples. And while these pseudo-gynecomastias or lipomastias may be totally benign, the humiliating "chest fat" is oftentimes just a companion or forerunner of pathological changes in the neighboring breast tissue.

A necessarily incomplete overview of the worst offenders

In the following overview that does not make any claims of being complete, I will thus not even try to make predictions like "... is more likely to cause lipomastia" or "... will rather induce gynecomastia". Moreover, you should also keep in mind that all of the pathologies, drugs and supplements can contribute to the development of gynocomastia, lipomastia and plain "chest fat", yet none of them, not even those for which a causal relationship has been established, will inevitable lead to the growth of the highly unaesthetic and potentially hazardous tissue overgrowth in the chest area!

Pathologies / diseases that are commonly associated with abnormal fat deposition, lipomastia and gynecomastia in men:

• Hypogonadism - Often but not always characterized by increased FSH, LH and SHBG levels and decreased total and free testosterone, as well as DHEAS levels; one of the most common non-environmental / drug-related reasons is Klinefelter' syndrome, a condition in which men have an extra X chromosome and which is usually associated with hypogonadism and reduced fertility (Yazici. 2010)
• Obesity - Obesity can contribute to the development of gyno- and even more lipomastia. In that it is not certain whether it is just a corollary factor with hypogonadism as the common denominator, or contributes directly to the development of unaesthetic and/or pathological changes in the breast tissue through an increased aromatization of testosterone into estrogen in the abundant adipose tissue (Wake. 2007)
• Liver cirrhosis - A cirrhotic liver (either due to alcohol or NAFLD) cannot metabolize the sex steroids properly. This does often result in low free testosterone and high estrogen levels, which can cause increases in chest fat or an enlargement and / or cancerous growth of the breast tissue (Cavanaugh. 1990). Similar effects could by the way arise from the (over-)use of supplements, such as berberine, quercitin, naringine, piperine, schisandra etc., which mess with the cytochrome P450 cascade, an enzymatic cascade that is responsible for metabolizing drugs and hormones (e.g. Gurley. 2012; Guo. 2012; Ho. 2000).

While the former were more or less "organ-related" causes of gynecomastia, the following list contains a handful of drugs that have scientifical evidence to back their causal involvement in the etiology of gynecomastia:

• Anabolic steroids & prohormones - Either due to increased estrogen levels on cycle, hormonal shut-down and hypogonadism or hormonal imbalances after the cycle, use of compounds that have the potential to induce gynecomastia in PCT (see "hormonal agents" in list below) or (possibly) direct or indirect effects on prolactin (see red box above)
• Other endocrine agents - Bicalutamide, Diethylstilbestrol, Dutasteride, Ethinylestradiol, Finasteride, GnRH, Goserelin, Leuprorelin
• Drugs for gastrointestinal disorders - Metoclopramide
• Diuretics - Spironolactone

In view of the fact, that most people will be aware of the dangers, it yet questionable in how far the commonly overlooked / largely unknown drugs and other offenders with less, but still existend scientific evidence to bolster their involvement in the development of abnormal fat deposition, lipomastia and gynecomastia in men do not pose a much greater threat. You should thus better beware of these:

• Statins - Roberto et al. report a significantly higher incidence in male gynecomastia among statin users (Roberto. 2012). Interestingly, the relative increase in risk correlated with the ability of the respective drug to inhibit HMG-CoA, or, if you will, it's potency. Intriguingly, gynecomastia is rarely mentioned as one of the myriad of potential side-effects of statin treatment, although the non-corrected incidence rate in the database records Roberto et al. analysed was 1/68 - with 25% of the US population in the 45+ age range being "on a statin", this would translate into roughly 1Mio! cases of statin unduced gynocomastia among the baby boomer generation, alone (this calculation assumes that there are ~70Mio babyboomers, which would be in accordance with data from census.gov). You should also keep in mind that if statins can do that supplements, like red yeast rice, which is actually nothing but a natural statin, are likely to be able to induce gynecomastia, as well.
• Proton pump inhibitors - Omeprazole, Ranitidine & co.
• Antineoplastic agents & Calcium channel blockers - Estramustine, Imatinib, Mandipine, Nicardipine, Nisoldipine, Nitrendipine
• Antivirals & -mycotics - Didanosine, Efavirenz, HAART, Indinavir, Ketoconazole, Nevirapin,
• Lipid modifying drugs - Bezafibrate
• Diuretics - Eplenerone, Bumetanidine
• Hormonal agents - Chlormadinone, Clomiphen, Cyproterone acetate, Follicle-stimulating hormone, HCG, Medroxyprogesterone acetate
• Immunosuppressants - Cyclosporin
• Psychoanaleptics & Psycholeptics - Fluoxetine, Haloperidol, Olanzapine, Risperidone, SSRIs, Sulpiride

Despite the fact that for many of these drugs the exact mechanisms have not yet been elucidated, it is likely that in most cases their "pro-gyno effect" is a downstream result of impairments of the HTPA (hypothalamic-thyroid-pituitary-axes), liver function or both and thus eventually mediated by the same fundamental hormonal imbalances that were discussed in the second paragraph of this article.

Prevention is #1, but sometimes treatment is inevitable

Even if you don't have a plenty of skeletons in your closet, no history of legal or illegal drug abuse, no diet-induced NAFLD, are lean, don't use truckloads of useless supplements etc., puberty and "bad genes" alone could have left you with a batch of unwanted tissue in a place where it certainly does not belong. In this case, avoiding all the 45+ aforementioned factors may help not to make things even worse, it will yet not make those ugly little bastards disappear over night; and I guess that alone should be reason enough to come back for part II of this series, in which we are going to take a look at potential treatment strategies - including, but not limited to classic surgical interventions.

Creatine for Type II Diabetics? 5g/Day Augment Exercise Induced Improvements in Glucose Disposal and Reduce Hb1Ac Levels by Increasing AMPK and GLUT-4 Expression

Image 1: A reasonable carb intake, regular exercise and, interestingly, creatine will help you not to become insulin resistant in the first place.

I don't know if you remember my rant against statins being promoted as unproblematic and healthy, when, at the same time, mainstream media portray creatine as a "dangerous gateway drug to steroids" (cf. "Statins Increase Diabetes Risk by >50%"). Today's blogpost is sort of an unintended follow-up on the former. After all the "dangerous gateway drug" just turned out to be useful in the treatment of the side-effects of the allegedly life-saving HMG-CoA reductase inhibitors (=statins).

A teaspoon of creatine a day keeps metformin away!

In the latest issue of the journal Amino Acids Christiano Robles Rodrigues Alves and his colleagues from the School of Physical Education and Sports at the University of Sao Paulo in (guess where ;-) Sao Paulo, Brazil, present the results of a double-blind randomized controlled trial involving "25 non-vegetarian type 2 diabetic patients", who received either 5g/day creatine monohydrate or placebo for 12 weeks. In addition, the obese (BMI: 32.5kg/m²) men and women had to take part in a twice-weekly exercise regimen, of which I assume that it revolved around relatively light cardiovascular type of exercises, because otherwise the scientists would probably have provided some more details on what exactly the subjects did.

Figure 1: Macronutrient composition (in g) of the (ad-libitum) diets of the study participants at the beginning and end of the 12-week creatine/placebo + exercise intervention (data adapted from Alves. 2012)

As you can see in figure 1 the nutrient intake (in g) at baseline and after the study was comparable. With respect to the carbohydrate intake, which has as of yet still not been officially accepted as a contributing factor to the progressio, not resolution, of diabetes, it should yet be said that the -15% reduction in carbohydrate intake in the placebo group alone could have made a slight, yet probably not statistically significant difference in terms of the reductions in H1bAc levels (obviously not wrt to the total levels, since the reduced carbohydrate intake in the placebo group just "leveled the playing field", meaning that during the treatment period subjects in both groups consumed roughly 180g of carbohydrates per day).

Figure 2: Changes in AMPK-alpha expression (left) and changes in Hb1Ac expressed as a function of changes in AMPK-alpha in the creatine group (right; data adapted from Alves. 2012)

It is thusly all the more remarkable that there was still a pretty obvious correlation between the elevated intra-muscular AMPK-alpha levels (p = 0.06, the low statistical significance is mainly a results of the small number of subjects, where the one outlier in the creatine group (cf. figure 2, right) can make all the difference), which were measured based on biopsies from the vastus lateralis that were taken from 10 of the subjevts (5 men and 5 women) 72h after the last training and after an 8h fast (cf. figure 2, left) and the changes in H1bAc levels, an - at least in carboholics - pretty adequate measure of long-term blood sugar control (high levels indicate that the red blood cells have already been clogged with the glucose from the sugar water that flows through the veins of the ever-increasing number of (pre-)diabetics).


Hah? Doesn't creatine increase energy stores? How come it does increase AMPK, then?

As a diligent student of the SuppVersity you will have read about the creatine-induced increases in AMPK-alpha expression before (cf. "A Glimpse on Other AMPK Modulators"). Some of you may also have read the Bernado's question, how creatine, a supplement that is marketed for its ability to raise intra-cellular energy stores decreases AMPK, when the latter is the energy sensor of the cell. And in fact, this does sound somewhat counterintuitive at first, but if you think about "how" exactly creatine works, it makes perfect sense.

Note: It is somewhat unfortunate that the scientists did control which of the two AMPK-alpha isoforms (alpha-1 or alpha-2, cf. "AMPK Isoforms") were elevated in response to the creatine (+ "exercise") intervention. In view of the fact that the alpha-2 isoform appears to prevail in skeletal muscle, we may yet assume that those elevations in AMPK did probably not exert any direct negative effects on mTOR and subsequently the protein synthetic response to exercise - the fact that both AKT and MAPK expression were identical in both groups would support this notion.

Supplemental creatine (as monohydrate or whatever other form) has to be "phosphorylated" (bound to a phosphor molecule) by the creatine kinase enzyme to form the rapidly mobilizable energy reserve, of which you all know that it can help you to lift heavier and think faster (don't disregard the importance of creatine for bain health, cf. "Creatine for Brain Health")! The energy that is necessary to convert the unphosphorylated supplemental creatine molecules, as well as the phosphates that are necessary to "recycle" the used PCr (now likewise unphosphorylated creatine molecules) is derived from intramuscular ATP. This leaves us with a bunch of newly "energized" phosphocreatine (PCr) molecules and a similar amount of adenosine-di-phospate (ADP) molecules, the presence of which in the muscle has been identified as the main factor, which protects AMPK from dephosphorylation (= being active) and thusly facilitates all the beneficial down-stream effects on glucose uptake (most prominently an increased expression and translocation of the GLUT-4 glucose transporters on the cell membrane), the medical orthodoxy still believes to be an exclusive prerogative of biguanide based diabetes drugs such as metformin (Glucophage).

Wait! Does creatine hamper my gains then?

With AMPK being the opponent of the "muscle-building" mTOR complex, these results could suggest that taking creatine may actually blunt protein synthesis. Now, while that may be the case, if you let your muscles starve for glucose, the opposite will be the case when, there is enough muscle glycogen to replenish both, the ATP as well as the PCr stores, since more PCr will translate into increased workloads and those will in turn provide a more pronounced growth stimulus, which will then result in creatine's well-established multiplicative effects of creatine on exercise-induced skeletal muscle hypertrophy (Hespel. 2007).

With >50% Increased Risk to Develop New-Onset Diabetes, Statins are "Starter Drugs" for Post-Menopausal Women. Plus: Younger, Leaner & Asian Women at Greatest Risk

Image 1: A statin here, some metformin to keep the collateral at bay, add an ACE inhibitor and some anti-coagulant drugs and you have a delicious cocktail of highly profitable pharmaceuticals...

Do you remember how creatine has gotten a bad rep within the mass media, a few years ago? Initially touted as an over-the-counter "steroid" by a clueless journalist, the did not, as you would have expected backpedal, or at least forget about the whole thing, when some experts raised their hands and said: "Wait a minute! Creatine is a naturally occuring amino acid with thousands of studies backing its efficacy...", no, they just turned it around and said: "Look, this is how it goes: First creatine, then androstenedione, next real gear! This stuff is a starter drug which will make our youth go astray!" ... Today, or I should say, on January 9, 2012, a study on another, yet in the eyes of the press obviously way less "starter drug" has been published - the title: "Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women’s Health Initiative"

Keep an eye on your mommy, she might be doing drugs!

As a diligent student of the SuppVersity and thoughtful observer of the blogosphere, I probably won't have to tell you that taking a stating, although they could be life-saving for a infinitesimal percentage of the population, is not as good an idea as the luckily in this part of the world forbidden TV commercials will make. At least for women, the "preventive" use that is so highly advertised by the statin producing pharmaceutical industry, is associated with a 61% increase to develop new-onset diabetes (48% if in addition to age, race and ethnicity, education, cigarette smoking, BMI, physical activity, alcohol intake, energy intake, familiy history of diabetes, and hormone therapy were also considered as confounding factors in the calculation of the hazard ratio), in the 120,173 women without pre-existing cardiovascular disease in the enormous cohort of the Women's Health Initiative study.

Figure 1:  Risk of developing diabetes by statin use among women with and without medical history of cardiovascular disease at baseline; unadjusted, age-and race/ethnicity and multivariate (age, race/ethnicity, education, cigarette smoking, body mass index, physical activity, alcohol intake, energy intake, family history of DM, and hormone therapy use) adjusted hazard ratios (data adapted from Culver. 2011)

When all confounding factors (see brackets above) are considered the "additional" risk decreases (BMI, physical activity and hormone therapy are probably the culprits, here) and the inter-group difference vanishes, so that this leaves us with a ~50% increased risk to develop type II diabetes in a cohort of 153,840 women, whose mean age was 63.17 years - now, if one discarded that the data in column 2 of figure 1 is already age-adjusted you could well argue, that at this age, it is "just normal" to develop some blood sugar issues.

Figure 2: Association between new-onset diabetes risk and statin use at baseline within different age, race/ethnicity, and BMI subgroups of the 153,840 participants; data shown as unadjusted and multivariate (age, race/ethnicity, education, cigarette smoking, body mass index, physical activity, alcohol intake, energy intake, family history of DM, and hormone therapy use - age, race and BMI were obviously excluded in the respective subgroup analysis) adjusted hazard ratios (data adapted from Culver. 2011)

Aside from the fact that this is an absolutely idiotic, yet often uttered statement (I hear that esp. from people who are already "at that age" and unwilling to do something about their (pre-)diabetic state, by the way), the data in figure 2 shows quite clearly that the "younger" ladies are at particular risk to develop diabetes. Even after the aforementioned adjustments for BMI, physical activity and co. were made the hazard ratio (a measure of the increased risk, with 1.0 = normal and e.g. 1.5 = 50% increased risk) of developing new-onset diabetes was slightly higher (+3%). It would thusly be interesting to see the hazard ratios for pre-menopausal women, or even teens and twens, an increasing number of whom is put on a "live-saving" statin - at the latest, when their cholesterol levels surpass the repeatedly lowered "cut-off" limit of currently 240mg/dl (NHLBI. 2012).

If your mama takes statins is a "light-weight" (for her age) and from Asia or the pacific islands, you better get her some Metformin - she probably is going to need it soon...

If you further scrutinize the data in figure 2, it become pretty obvious that the group(s) with the highest risk to develop new-onset diabetes upon being treated with statins are

• women from Asia or the Pacific Islands, with an increased risk of +112% (unadjusted) and +78% (adjusted for the aforementioned variables except from ethnicity, obviously), and
   
• women with a BMI of <25 kg/m², with an increased risk of +240% (unadjusted) and +89% (adjusted for the aforementioned variables except from BMI, obviously)

Whether this would mean that light-weight Asians / Pacific Islanders who are put on statin therapy would be even more likely to develop new-onset diabetes, would admittedly need further elucidation.

Figure 3: Association between new-onest diabetes risk and statin use at baseline in 153,840 participants; data shown as unadjusted, adjusted for age / race /ethnicity and multivariate (details see figure 1) adjusted hazard ratios (data adapted from Culver. 2011)

It is however, at least in my mind, not unlikely - in particular if they are / are going to be on the statin for an extended period of time (cf. figure 3). Against that background it is quite comforting to know that most statin dealers... ah, pardon pharma companies, also have one, many even a whole host of diabetes drugs for doctors to chose from, when - after a few months of treatment - their formerly only "hypercholesterolemic" female patients have developed full-blown diabetes!

So, let's just hope that the sons and grandsons of these women did not resort to creatine or other dangerous "steroids" from their local GNCs by then! I mean, otherwise it would be likely that they were going on a "roid rage" against their mommy's and granny's doctors, when they see the muscles and brains of their insulin-dependent loved ones wither under the influence of their cholesterol lowering medication.