High Fat vs. High Carb and How the Tiny Word "Synthetic" May Turn Out to Be an Epic Game Changer That Puts a HUGE Question Mark Behind "If It Fits Your Macros"

Even if both "Fit Your Macros" you should know better than to select the "fruit" loops (where is the "fruit" in those loops anyway?).

A war is raging! Well, at least in the Internet the "battle" between the low-carb revolutionists and the low-fat veterans does sometimes in fact resemble an epic battle between god and evil... at least that's what the combatants believe.

As of late it seems as if the rebels, i.e. the low-carbers were getting the upper hand and that despite the constant supplies the low fat veterans are getting from their friends in the medical establishment - friends who pay for studies the veterans to agrue how stupid and off base the rebels' assumption that "low carbing" would help us to solve the obesity epidemic actually actually were.

Don't worry this post is not a war epic ;-)

I know, up to this point, all this may not have sounded much like a SuppVersity article, but this will change now that we are about to take a look at a soon-to-be-published paper by Bérengère Benoit et al. from the Lyon University (Benoit. 2013).

What do these Jerusalem artichokes, agave, bananas, burdock, camas, chicory, coneflower, costus, dandelion, elecampane, garlic,jicama, Leopard's-bane, mugwort, onion, wild yams, yacon and a whole host of other foods have in common? Right! They contain inulin. Whether you will be able to get a whopping amount of 10% inulin in your diet w/out the use of supplements or "enriched" foods, is yet as questionable as how beneficial this actually is for friends of physical culture (read more)

The French researchers started out with the hypothesis that the metabolic effects of a diet does not simply depend on its macro-nutrient composition. Instead, they made the SuppVersity standard assumption that the food quality is about as important as food quantity and assumed that negative effect of one of the standardized synthetic high fat rodent diets (sy-HFD) consumption would be

"[...]impacted by the choice of the control diet using 2 control diets that are typically used in HFD-induced obesity protocols. The specific research objectives were to test the impact of diets on typical parameters studied in HFD-induced obesity protocols: body weight gain, fat accumulation in tissues, alteration of insulin sensitivity, markers of inflammation, and markers of plasma endotoxemia." (Benoit. 2013)

And this means? Well, think about it as if you wanted to analyze the quality of the shiny new iPhone. Obviously, it will be all the shinier the trashier your baseline comparison is - right?

The French scientists assumed something very similar may apply for the high fat diets. Depending on whether you compare them to a "healthy" or a trashy diet, the outcome of your study and the message "Low carb is..." will be different. The same obviously goes the other way around. If you have a "high carb" diet that's all fructose and nothing else, your outcome will be different and you will draw different conclusions and may make diametrically opposed recommendation.

Ok, I got to be honest with you...

... this is not - at least not yet - the study that compares what you probably understand when I say "low carb" to what you probably think of, when I say "low fat". So this is not something like 25/5/70 (protein, carbs, fats) vs. 25/70/5 (protein carbs, fats). Rather than that, Benoit et al. used those "high fat" diets you see in 99% of the corresponding rodent studies. Diets that are high in both carbohydrates (45%) and fats (40%) - values expressed in weight units - and would thus imho qualify as "low protein" diets.

Figure 1: Differential effects of synthetic low fat (sy-LFD) and high fat diet (sy-HFD) on lean mass, fat mass, insulin, triglycerides, cholesterol and the amount of free fatty acids in the blood of the rodents; all data expressed relative to the corresponding values of the rodents in the regular chow group (Benoit. 2013)

What the researchers did though was to give their analysis a twist by including not one, but two control diets. One containing a synthetic and one containing natural low fat chow - both of them with identical macro-nutrient composition (18, 70, 12% - protein, carbs, fats), but with the former, the synthetic low carb chow being based on the same artificial (in this case this just means that the combination of nutrients was artificial and would not occur like that in nature) ingredients as the synthetic high fat diet.

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This is hilarious, right? Identical macro make, up totally different results? Yep, that's right and it should be reason enough for us to look into the differences. So let's see what we've got

• 

  According to Wood et al. (1988) black pepper contains between 3-8% piperine. This means that 4 teaspoons of it should help you combat abdominal fat (-16% on cornstarch diet in rodent study) - at least according to these previously reported results.

  Barley, wheat, corn, those are the main carbohydrate sources in the regular low fat chow. In the synthetic diet, however it's corn starch, succrose and a tiny bit of lactose.
• Soybean (not oil, but whole!) and fatty fish solubles, those are the main fat sources in the natural diet. The synthetic diet on the other hand contains soy bean oil, lard and milk fat.
• Wheat bran that's the major source of fiber in the natural diet. It's synthetic counter-part on the other hand features pure wood aka cellulose. 
• Inert proteins, i.e. those which are already present in the plant material in the regular chow diet are the only protein sources in the regular diet. The synthetic diet on the other hand features casein of which numerous previous studies have shown that it appears to promote the mass (lean and fat) accrual in rodents.

It is thus quite obvious: Hitting your macros is not all that counts. It's not all that counts for rodents and you can bet that it ain't all that counts for human beings.

So what's the real take home message then?

• From a science perspective: At least the rodent-part of the (hi-)story about the good and bad effects of low fat and/or low carb diets does have to be rewritten, now that we know that we have been fooling ourselves with figures that are worthless unless you know exactly what (which foods) they represent. Ever since the late 1990s we know for example that a "natural" high fat diets with a high amount of whole eggs will delay (not accelerate) the natural decline in insulin sensitivity and that in rats (Berdanier. 1998)!
  
  So, have the synthetic rodent diets fooled us? Probably yes. And what about the synthetic Standard American Diet? Well, it may not have fooled, but certainly killed us - at least several millions of us.
   
• From a real world perspective: Actually I already said, it, but I guess I will simply repeat that quality counts and macros are nice numbers with little meaning without at least a broad guideline (like: "Eat whole foods only!") on where you get them from.

Personally, I am curious whether anyone will actually take the results of this study at heart and finally throw the synthetic rodent chow away... you don't think so? Well, me neither.

References: 

• Benout B, et al. High-fat diet action on adiposity, inflammation, and insulin sensitivity depends on the control low-fat diet. Nutrition Research. 2013 [epub ahead of print]
• Berdanier CD, Kras KM, Wickwire K, Hall DG. Whole-egg diet delays the age-related impaired glucose tolerance of BHE/Cdb rats. Proc Soc Exp Biol Med. 1998 Oct;219(1):28-36.
• Wood AB, Barrow ML, James DJ.  Piperine determination in pepper (Piper nigrum L.) and its oleoresins - a reversed-phase high-performance liquid chromatographic method. Flavour Fragr. J., 3: 55–64.

The Satiating Secret of Arginine, Lysine and Glutamic Acid. Plus: Things You May Not Know About These Aminos

No, no and no. No amino acids = no satiety = no weight loss.

Personally, I have never been interested in products that would increase satiety. Being a born masochist, at least, when it comes to cutting body fat, I always liked being hungry... well, at least until I had to learn that there is an intricate hormonal connection between "being hungry" and the diet-induced reduction in metabolic rate, hormonal production etc. That changed my whole perspective on agents that increase satiety completely, and I started to read read papers like the one Jordi et al. are about to publish in one of the upcoming issues of the Journal of Physiology (Jordi. 2013).

The satiety shoot-out

According to the researchers from the University of Zurich, the top-dogs, or rather the most satiating among the so-called proteogenic amino acids, which are ...

• L-Leucine (Leu / L)
• L-Lysine (Lys / K)
• L-Methionine (Met / M)
• L-Phenylalanine (Phe / F)
• L-Proline (Pro / P)
• L-Serine (Ser / S)
• L-Threonine (Thr / T)
• L-Tryptophan (Trp / W)
• L-Tyrosine (Tyr / Y)
• L-Valine (Val / V)

• L-Alanine (Ala / A)
• L-Arginine (Arg / R)
• L-Asparagine (Asn / N)
• L-Aspartic acid (Asp / D)
• L-Cysteine (Cys / C)
• L-Glutamic acid (Glu / E)
• L-Glutamine (Gln / Q)
• Glycine (Gly / G)
• L-Histidine (His / H)
• L-Isoleucine (Ile / I)

... are L-arginine (Arg), L-lysine (Lys) and L-glutamic acid (Glu). The Swiss scientists were able to demonstrate that these three amino acids induced neuronal activity in the area postrema and the nucleus of the solitary tract. That sounds funky, but non-significant, right? Well, it wouldn't be, as long as you did not take into consideration that we know from previous studies that these brain regions are responsible for the regulation of energy intake - specifically our appetite for more.

Additional info: Just to complete the list, I want to add a non-proteogenic amino acid (an amino acid that is not used by the body to "build" proteins) with profound satiety effects. One you actually have heard about several times in the past weeks: Taurine! In 2012 Solon et al. published a study that shows quite conclusively that taurine, once it crosses the blood brain barrier, will reduces food intake, but also locomotor activity in rodents (Solon. 2012). As the scientists point out, These effects are accompanied by the modulation of expression of the "satiety hormone" NPY.

L-arginine has research to support its use as anti-diabetic weight-loss adjuvants (learn more); and the results of the study at hand suggest that its benefits may be mediated by its effects on the brain & gut.

From a "what are the downstream effects on my metabolism"-perspective, however, it may in fact be even more important that the amino acids also provoked an increase in gastric distension by differentially altering gastric secretion and/or emptying. After all, ...

"[...] these peripheral mechanical vagal stimuli were dissociated from the amino acids' effect on food intake. [So that it is prudent to assume that] Arg, Lys and Glu had a selective impact on food processing and intake suggesting them as direct sensory input to assess dietary protein content and quality in vivo. " (Jordi. 2013; my emphasis)

In other words: L-arginine, L-lysine and L-glutamic acid are not simply going to reduce your cravings they will also tell your body: Hey there's some good quality protein coming in.

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Hold on! Where are the proven benefits? I have to admit all that sounds as if it would be of questionable relevance but any SuppVersity reader for whom this is not the first visit to this webpage will probably have read about the surprisingly profound weight loss benefits of L-arginine, which have only recently been tracked down to its interactions with the GLP-1 one of the so-called satiety proteins with far-reaching downstream effects on glucose and fatty acid metabolism (learn more about the fat burning prowess of L-arginine).

As far as glutamic acid is concerned, it may be worth mentioning that Freiberg et al. reported more than 20 years ago that certain glutamic acid derivates can act directly on the cholecystokinin receptor, which is - along the the PYY receptor one of the major "You are full! Now stop eating"-switches of the mammalian body (Freiberg. 1990).

Figure 1: AUC in response to ingestion of 25g of glucose or water w/ or w/out 150mg/kg lysine (Kalogeropoulou. 2009)

Similarly unknown as the involvement of glutamic acid in the concert of satiety hormones is the effect lysine (150mg/kg) had on the glucose, insulin and glucagon resonse of healthy volunteers, when Kalogeropoulou et al. administered it either alone or in conjunction with 25g of glucose to thirteen healthy volunteers, where it triggered an increase in glucagon and insulin, when it was administered alone and significant reduction in the blood sugar response, when it was administered in conjunction with the 25g of glucose (Kalogeropoulou. 2009). Interestingly the increased glucsose disposal did not depend on an increase in insulin, so that it must be related to downstream improvements in insulin sensitivity and the efficacy of glucose uptake.


References:

• Freidinger RM, Whitter WL, Gould NP, Holloway MK, Chang RS, Lotti VJ. Novel glutamic acid derived cholecystokinin receptor ligands. J Med Chem. 1990 Feb;33(2):591-5.
• Kalogeropoulou D, LaFave L, Schweim K, Gannon MC, Nuttall FQ. Lysine ingestion
  markedly attenuates the glucose response to ingested glucose without a change in
  insulin response. Am J Clin Nutr. 2009 Aug;90(2):314-20.
• Jordi J, Herzog B, Camargo SM, Boyle CN, Lutz TA, Verrey F. Specific Amino Acids Inhibit Food Intake via the Area Postrema or Vagal Afferents. J Physiol. 2013 Jul 29. [Epub ahead of print] 
• Solon CS, Franci D, Ignacio-Souza LM, Romanatto T, Roman EA, Arruda AP, Morari J, Torsoni AS, Carneiro EM, Velloso LA. Taurine enhances the anorexigenic effects of insulin in the hypothalamus of rats. Amino Acids. 2012 Jun;42(6):2403-10.

Cinnamon, Curcumin (Turmeric), Licorice (Glycyrrhizin), Melatonin, Milk Thistle (Silymarin). Supplements to Improve and Restore Insulin Sensitivity - Serving #3

Sleep hygiene was part of the lifestyle tips in the first episode of this series, with this episode you get a tool that can help you get back into the groove: melatonin.

This is Sunday number three with supplements that may help you improve / maintain your glucose sensitivity and I can already tell you it's going to be the last one. In other words, if there are any compounds that have not yet been covered in this series - just a reminder

• Alpha Lipoic Acid, GABA, Taurine, Green Tea, Gooseberry & Fenugreek were addressed in detail as part of supplement list #1
• Berberine, Banaba (Corosolic Acid), Rauwolfia Serpentina, (Apple Cider) Vinegar, Chromium were addressed in detail on supplement list #2 

- this is your last chance to make a wish! So, if you have something special in mind, use the comment section at the end of this article and tell me which agents you want to see in issue #4 on next Sunday.

Ah, ... it should be obvious that none of the following agents qualifies: Cinnamon, Curcumin (Turmeric), Licorice (Glycyrrhizin), Melatonin, Silymarin - why? Well those are the ones you can read about in the paragraphs below :-)

• Dosages for cinnamon supplements range from 1-6g+ of pure real cinnamon (cinnamomum vera) to 150-500mg of extracts (depending on their quality). You should be aware though that "fake" cinnamon (cinnamomum cassia, which is sold in the US simply as "cinnamon") contains (highly variable amounts) of coumarin a liver toxic and carcinogenic substance w/ an upper intake limit of 0.07mg/kg body weight that may easily be exceeded by eating common foodstuffs like oatmeal with cinnamon in small children (Fotland. 2012).
  

  According to Fotland et al. this can lead to toxicity reactions within weeks. So don't be cheap and better make sure not to buy "fake cinnamon" (=cassia) for you or your kids and loved ones.
  Cinnamon (Cimmomium verum!) [B]: Cinnamon is unquestionably one of the best known supplements for diabetics. "High blood sugar? Have some cinnamon in your sugar-laden Starbucks coffee!"... and this is exactly where the problem is. Everyone knows that cinnamon works - acutely(!), because he or she can measure his blood glucose after the ingestion of the said Starbucks coffee with and without cinnammon, but...
  1. according to the latest meta-analysis the long-term benefits of using cinnamon to manage blood glucose levels in type II diabetics are zero - the most important measure of their overall glycemic status, i.e. HbA1c, does not change significantly; or I should say: it reacts formidable in studies lik Lu et al. (2012; 120 or 360mg/day treated alongside standard diabetes drug) and deteriorates in others (Mang. 2006; Wainstein. 2011; etc.)
  2. studies in healthy individuals suggest that the blood glucose lowering effects are a mere results of an inhibition of the digestion and absorption of high GI carbs (6g regular cinammon w/ rice or pudding; Hlebowicz. 2007)
  There is however recent evidence that some of the secondary plant material, i.e. the proanthocyanidins you will find in cinnamon water extracts exert a direct protective effect on stressed pancreatic beta cells.
  Just a note for those who feel I am a "supplement hater": I am not the only one displaying a healthy degree of skepticism towards the hoopla that surrounds the use of cinnamon as an anti-diabetic. The "gold standard" review from the Cochraine Foundation says: "There is insufficient evidence to support the use of cinnamon for type 1 or type 2 diabetes mellitus. Further trials, which address the issues of allocation concealment and blinding, are now required. The inclusion of other important endpoints, such as health-related quality of life, diabetes complications and costs, is also needed" (Leach. 2013)
  Overall, cinnamon is thus a "B" as in "one of the B-est agents to protect yourself from developing insulin resistance and diabetes": It can also be interesting for type II diabetic looking to improve his blood lipids, but this is a different topic (cf. Khan. 2003). So, if you can't keep away from the sweet stuff of which you know ever since episode 1 of this series that you are not supposed to eat it, some cinnamon won't hurt - if you hate the taste, though, don't force it down. It's not really worth gagging.

• 

  In healthy human beings the administration of 6g of curcuma longa before a 75g glucose tolerance test does just one thing: It spikes insulin without improving the glucose uptake. Technically this is a decrease - not an increase in insulin sensitivity, which would have to be observed if curcumin was an insulin-sensitizer.

  Curcumin (Turmeric; curcuma longa) [C] - Curcumin is probably among the hottest supplements out there. Everybody appears to know exactly what it does and obviously everything is ueber-potent and super-healthy. It does therefore appear almost unquestionable that curcumin is going to help with insulin resistance, as well... right? Well, unquestionable as it may apper, the mere assumption that it would do so is not just unwarranted, but downright misleading.
  
  While there is evidence that its anti-inflammatory effects can help restore normal insulin sensitivity in diabetic individuals and animals, such as the streptocitozin-induced diabetic rodents in a 2011 study by Na et al., the important evidence from human studies is not there. In fact, in a 2010 study from the Skåne University Hospital in Sweden, Wickenberg, Ingemasson and Hlebowicz were able to show that curcumin worsens the insulin sensitivity of fourteen healthy subjects.
  
  Being first and foremost and anti-inflammatory agent, it is at imho not surprising that curcumin is not the ideal insulin sensitizer. In view of the fact that the obese and inflamed may need a little help to get their baseline inflammation back in check, before any "anti-diabesity" agent may even start working curcumin does however still qualify as a "C" as in "take in C-ombination" with other agents, but only if you're actually dealing with inflammatory problems (e.g. high CRP-1 value in serum; type 1 diabetes and problems with heme oxygenation, cf. Aziz. 2013). After all, the emerging role of reactive oxygen specimen in muscule- and thus tissue- and anti-obesity-specific glucose uptake clearly suggest that the suffocation of all inflammatory signals is not going to help, but hinder glucose uptake (Merry. 2012).
• Licorice (glycyrrhizin) [D] - While it has a bad rep as a "cortisol increasing" agent that puts you at risk of developing high blood pressure glycyrrhizin does actually have the ability to reverse diet-induced insulin resistance and get the GLUT-4 glucose transporters back out on the cell surfaces. Sil et al., for example report that they observed corresponding improvements of insulin sensitivity in a rodent model of high frutcose feeding (which is actually not much different from the average victim of the American diet; dosage was 50mg/kg or 600-750mg/day for a human being; Sil. 2013)

  

  Table 1: Analysis and comparison of active ingredients in Radix Glycyrrhizae (licorice) from Europe and China by capillary-zone electrophoresis (Rauchensteiner. 2005)

  As you can see in the table above the glycyrrhizin content of different forms of licorice is somewhere between 2-3mg/100mg (Rauchensteiner. 2005). In other words, to hit the 600-750mg you will necessarily need an extract - unless you want to consume kilograms of licorice.
  
  

  

  What about testosterone? A larger scale 4-week trial with 100g/day of licorice containing 0.15% glycyrrhizic acid could not find any significant changes in sex steroid hormones (Sigurjonsdottir. 2005)

  Whether that's a smart thing to do is however questionable, as licorice does not just have the potential to increase blood pressure, but is also a relatively unpredictable agent. Most of the glycyrrhizin will never even make it through the gut and into your blood, but rather be converted to other metabolites by your gut microbiome. Injections on the other hand appear to be possible, but the example of a 72-year old subject of a case report from the year 2000 goes to show you that in some cases the anti-diabetic effects may be a tad bit to potent. The subject did after all end up being profoundly hypoglycemic after the injection of 80mg of glycyrrhizin (Motoo. 2000).
  
  Despite potential anti-diabetic effects (read more) and the potent anti-obesity effects (3g of licorice per day = 2% body fat reduction in normal weight volunteers w/out dietin → learn more) you have read about here at the SuppVersity licorice does therefore get a "D" as in "D-on't take", because it seems as if the margin between 'enough to elicit beneficial effects' and 'so much that you are risking side effects' is pretty narrow.

• 

  Melatonin has also been shown to have beneficial effects on glucose uptake and glycogen synthesis after exercise and scientists speculate that it could play a major (facilitative) role in skeletal muscle adaptation to exercise (learn more)

  Melatonin [C]- I know, I know, it's a "dangerous hormone" ... well, nobody will propose that, when we talk about prescribing verifiably more dangerous oral contraception to women. I wonder how that is!? After all, this "dangerous hormone" could, mitigate the negative side effects many of the oral contraceptive appear to exert on the glucose metabolism of young, previously healthy women (for an in-depth discussion see Lopez. 2012). Ah, I am digressing, once again. So let's get back to melatonin.
  
  Assuming you follow all the recommendations from installment 1 of this series you should not be in dire need of melatonin supplementation. Sometimes, however, life comes in the way - for me that happened in the course of the last weeks. Oftentimes it's not even necessarily the "bad things" in life that keep you from getting enough sleep and producing a truckload of endogenous melatonin. It is in these situation, where some supplemental help in pill- or capsule-form may in fact come extraordinarily handy as an acute treatment that will work by its beneficial effects on skeletal muscle glucose uptake (Ha. 2006), leptin expression in response to insulin (Alonso-Vale. 2005) and 24h glucose homeostasis (la Fleur. 2001)
  
  In view of its many-fold effects on the mammalian metabolism and the age-related decline in melatonin production, it is actually not surprising that the provision of melatonin to aging rodents (0.4μg/ml in drinking water) was able to restore plasma insulin and leptin levels to youthful levels and continued treatment until old age maintained suppression of visceral (retroperitoneal + epididymal) fat levels without any effects on plasma corticosterone and total thyroxine (T4),  testosterone, insulin-like growth factor I (IGF-I) and total triiodothyrone (T3) compared to placeo (Rasmussen. 2002)
  
  That being said, for young(er) individuals, it may be sufficient to restore a normal circadian rhythm by strategically supplementing at the right times. In conjunction with a consequent "lights out strategy" (learn more), this should get you back on track and your insulin resistance up. Melatonin is thus a classic "C" as in "C-an be used by everyone"; a "C" that does however need some basic information about when you want to take the 1-10mg of melatonin to derive the greatest benefits (learn more about phase shifting your circadian rhythm) .
• Silymarin (Milk thistle) - Not exactly one of the agents you would expect on a list like this, but contrary to many better known anti-diabetic agents milk thistle can - just like cinnnamon, by the way - inhibit the accumulation of human islet amyloid polypeptide in the pancreas and the subsequent development of the end stages of diabetes (=the inability to produce insulin). In a 2006 study from Iran the provision of milk thistle to type II diabetics (200mg silimarin, 3x daily) lead to significant reduction in acute (blood glucose) and long-term measures of (HbA1c) of glucose management, as well as improvements in insulin levels (see figure below).

  

  Changes in fasting blood sugar (FBS), long-term marker of FBS (HbA1c) and insulin levels in randomized controlled trial w/ 51 type II diabetics; data expressed relative to median values across all groups (Huseini. 2006)

  In view of the results from the randomized controlled human study depicted in the figure above and based on the fact that silybin / silymarin / milk thistle helps controlling NAFLD, of which you learned earlier this week that it may as well be the cause not the consequence of insulin resistance (learn more). Milk thistle deserves a "B" as in "B-etter than many more specific agents". Dosages range from 500-1,500mg per day and you should make sure you get a standardized product and not an extract with non-disclosed amounts of active ingredients in it.

I know there are more agents, but I do also know that I cannot address each and every herb that may have the potential to reduce your blood glucose levels by 1pt. So unless you want me to make the last five picks, take your chance and let me know which agents you are still missing in the comments.

References:

• Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med. 2013 Sep-Oct;11(5):452-9.
• Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves Borges-Silva C, Neto JC, Lima FB. Melatonin enhances leptin expression by rat adipocytes in the presence of insulin. Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E805-12.
• Aziz MT, El Ibrashy IN, Mikhailidis DP, Rezq AM, Wassef MA, Fouad HH, Ahmed HH, Sabry DA, Shawky HM, Hussein RE. Signaling mechanisms of a water soluble curcumin derivative in experimental type 1 diabetes with cardiomyopathy. Diabetol Metab Syndr. 2013 Mar 12;5(1):13.
• Fotland TØ, Paulsen JE, Sanner T, Alexander J, Husøy T. Risk assessment of coumarin using the bench mark dose (BMD) approach: children in Norway which regularly eat oatmeal porridge with cinnamon may exceed the TDI for coumarin with several folds. Food Chem Toxicol. 2012 Mar;50(3-4):903-12. 
• Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, Baik HH. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006 Aug;41(1):67-72.
• Hlebowicz J, Darwiche G, Björgell O, Almér LO. Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects. Am J Clin Nutr. 2007 Jun;85(6):1552-6. 
• Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res. 2006 Dec;20(12):1036-9.
• Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003 Dec;26(12):3215-8.  
• la Fleur SE, Kalsbeek A, Wortel J, van der Vliet J, Buijs RM. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J Neuroendocrinol. 2001 Dec;13(12):1025-32.
• Lopez LM, Grimes DA, Schulz KF. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database Syst Rev. 2012 Apr 18;4:CD006133.
• Lu T, Sheng H, Wu J, Cheng Y, Zhu J, Chen Y. Cinnamon extract improves fasting blood glucose and glycosylated hemoglobin level in Chinese patients with type 2 diabetes. Nutr Res. 2012;32(6):408-412.
• Mang B, Wolters M, Schmitt B, Kelb K, Lichtinghagen R, Stichtenoth DO, Hahn A. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipids in diabetes mellitus type 2. Eur J Clin Invest. 2006 May;36(5):340-4. 
• Merry TL, McConell GK. Do reactive oxygen species regulate skeletal muscle glucose uptake during contraction? Exerc Sport Sci Rev. 2012 Apr;40(2):102-5. 
• Motoo K et al. Non-insulin-dependent Diabetes Mellitus in an Elderly Patient with Hypoglycemic Attacks Induced By Glycyrrhizin Administration. Journal of the Japan Diabetic Society. 2000; 42(8).
• Na LX, Zhang YL, Li Y, Liu LY, Li R, Kong T, Sun CH. Curcumin improves insulin resistance in skeletal muscle of rats. Nutr Metab Cardiovasc Dis. 2011 Jul;21(7):526-33. doi: 10.1016/j.numecd.2009.11.009. 
• Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology. 1999 Feb;140(2):1009-12. Erratum in: Endocrinology 2002 Apr;143(4):1269.
• Rauchensteiner F, Matsumura Y, Yamamoto Y, Yamaji S, Tani T. Analysis and comparison of Radix Glycyrrhizae (licorice) from Europe and China by capillary-zone electrophoresis (CZE). J Pharm Biomed Anal. 2005 Jul 15;38(4):594-600.
• Sigurjonsdottir HA, Axelson M, Johannsson G, Manhem K, Nystrom E, Wallerstedt S. Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders. Horm Res. 2006;65(2):106-10.
• Sil R, Ray D, Chakraborti AS. Glycyrrhizin ameliorates insulin resistance, hyperglycemia, dyslipidemia and oxidative stress in fructose-induced metabolic syndrome-X in rat model. Indian J Exp Biol. 2013 Feb;51(2):129-38.
• Wainstein J, Stern N, Heller S, Boaz M. Dietary cinnamon supplementation and changes in systolic blood pressure in subjects with type 2 diabetes. J Med Food. 2011;14(12):1505-1510.
• Wickenberg J, Ingemansson SL, Hlebowicz J. Effects of Curcuma longa (turmeric) on postprandial plasma glucose and insulin in healthy subjects. Nutr J. 2010 Oct 12;9:43.

Gluten Free, But not Suitable For Celiacs: Milk, Chocolate, Corn, Instant Coffee and 20 Other Foods & Food Ingredients That Could Cross-React With Gluten Anti-Bodies

Unless you got the right, i.e. breast milk as a baby and have rendered your gut "gluten proof" - being breast fed, when you are first exposed (or being exposed later in life) has after all been suggested as a protective factor (Farrell. 2005)

This is not going to be a long post; and still, at least for some of you it is going to be an important post. A post that may have the potential to change your life for the better or for the worse depending on whether you actually suffer from gluten-intolerance or have simply been bamboozeled by the "gluten is the devil" messages that are plastered all over the Internet these days.

Actually, I would hope that you belong to neither of the groups and can thus simply ignore this post. For the unfortunate rest, I have prepared a mini-summary of the results of a recent study from the Immunosciences Lab in Los Angeles (Vojdani. 2013)

Milk and cornflakes - a killer combo

A couple of recent studies, as well as reports from patients all of which clearly suggested that "being gluten free" does not equal "being symptom free" had spiked the researchers interest. Was it possible that the persistent symptoms were brought about by cross-reactions between the anti-bodies that would usually attach to the gluten proteins to trigger an immune reaction and other molecules? Molecules from such innocent foods, as dairy, chocolate, and even coffee!?

Suggested read: "Leaky Gut & Gluten Belly: Bacterial Firebugs Translocate from Your Gut to Your Ever-Growing Visceral Fat Depots" | read more

"[W]hen histological response was assessed in celiac patients after 6 months of following a GFD [gluten free diet], complete normalization and reconstruction of villous architecture was observed only in 8% of individuals, while 65% of these patients were in remission and 27% did not respond to GFD and had no observable change in their clinical symptoms (Lanzini. 2009).

The lack of improvement in histopathology and clinical symptomatology in a subgroup of patients on a GFD may be associated with dietary non-ad-herence or cross-reactive epitopes triggering a state of heightened immunological reactivity in gluten-sensitive individuals (Hadjivassiliou. 1997)." (Vojdani. 2013)

The hypothesis certainly isn't totally odd. Kristjansson et al. were for example able to show that 50% of their celiac patients experienced a significant mucosal inflammatory response similar to that elicited by gluten, when they were exposed to cow’s milk protein. Of the 15 healthy controls in their study, however, not a single one showed the slightest signs of auto-immune related inflammatory processes (Kristjansson. 2007).

So is this "real" celiac disease?

It should be obvious though that the corresponding "cross reactive" agents do not induce celiac disease (which is per definition an auto-immune disease that's triggered by the reaction to gliadin). They are however well able to alter the intestinal barrier integrity - a symptom that is also one of the key feature of the early stages of celiac disease.

Figure 1: Reaction of affinity-purified α-gliadin 33-mer polyclonal antibodies to gliadin and different food antigens; data in large figure relative to control, data in small inset relative to a-gliadin (Vodjdan. 2013)

If full remission of celiac disease cannot be achieved even on gluten-free diet, the underlying reason may thus well be the presence of peptides and antigens that (cross-)react with the same anti-bodies the body of celiac patients produces against the α-gliadin 33-mer peptide aka gliadin. Scientists even speculate that the co-exposition to these agents could eventually lead to the establishment of "new" auto-immune diseases and food allergies and some argue that the ever-increasing spectrum of allergies is partly a result of untreated autoimmune reactions which are then "spreading" to other previously well-tolerated foods and food ingredients.

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Suggested read: "Beyond Celiac: Study Sheds New Light on Obesogenic Effects of Gluten - Are PPARs & Bacteria Both Involved?" | read more

The problem seems real, if you're really gluten intolerant: With milk, all sorts of dairy products (including whey), instant coffee (but not espresso; see small inset), avenin containing oat products (unfortunately, I cannot tell you how you can recognize the "unproblematic" oats at the super market, but if you google "avenin-free oats" you will see a couple of products and stories pop up; Comino. 2011) and corn having a significant potential for cross-reactivity, it appears almost reasonable that some people come back from their visit with a mostly self-proclaimed expert in all things celiac with an endless list of items they are not supposed to eat and a tiny 5-item list of foods they are supposed to live on for the rest of their lives.

What is not reasonable, however, is that this is the case for more and more people who are basically asymptomatic... well, aside from their "inability to lose weight" that is obviously not related to their "inability to exercise" and their "inability to stop watching TV and browsing the Internet for easy quick-fix solutions to obesity problems", but most obviously be brought about by gluten intolerance ;-(

References:

• Comino I, Real A, de Lorenzo L, Cornell H, López-Casado MÁ, Barro F, Lorite P, Torres MI, Cebolla A, Sousa C. Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease. Gut. 2011 Jul;60(7):915-22.
• Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, Gibson A, Grünewald RA, Lobo AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry. 1997 Dec;63(6):770-5.
• Kristjánsson G, Venge P, Hällgren R. Mucosal reactivity to cow's milk protein in coeliac disease. Clin Exp Immunol. 2007 Mar;147(3):449-55.
• Lanzini A, Lanzarotto F, Villanacci V, Mora A, Bertolazzi S, Turini D, Carella G, Malagoli A, Ferrante G, Cesana BM, Ricci C. Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet. Aliment Pharmacol Ther. 2009 Jun 15;29(12):1299-308. 
• Vojdani A, Tarash I. Cross-reaction between gliadin and different food and tissue antigens. Food and Nutrition. 2013; 4:20-32.

Intermittent Fasting Ramadan Style: Lose More Than 3% Body Fat Off an Already "Lean" 31" Waist in 28 Days. Plus: Why Do the "Fast / Starve Two Times à Week" Diets Work?

Feasting and a wasp waist? Does bring the two together?

You are among the couple of thousand people who have been following the Intermittent Thoughts on Intermittent Fasting Series, here at the SuppVersity you will be aware that despite "fasting windows", "feasts" and "breakfast skipping" a religious fast as it is performed by Muslims all around the world may share several key elements with what fitness fanatics think about, when they hear the words intermittent fasting". There are however a couple of key differences of which you should be aware.

• rising before sunrise and having breakfast will minimize the fasting window - While most people I know personally don't do this, there are families, where everyone gets up before the sun rises to have breakfast. With the huge dinner before bed and a (usually smaller) breakfast right after you stand up in the early AM, the fasting window which would otherwise be up to 18h wide can become pretty narrow.
• not drinking during the fast - It is religious practice, so I am not in the position to criticize it, but for anyone fasting for health purposes not drinking anything during the fasting hours is absolutely not advisable.
• food / diet quality - The average Westerner will probably assume that the food quality sucks during Ramadan, after all the family-get-togethers are not exactly occasions to eat chicken, rice and broccoli, but compared to the regular diet of the inhabitants of the Western obesity belt the self-prepared meals from real food ingredients will probably still entail an improvement in overall diet quality for many people who are fasting for religious reasons.

I guess I could enumerate at least 3 additional factors you may want to keep in mind, when you take a look at the results of the Shruthi, Hassan and Reddy, three scientist from the Bhaskar Medical Colleg in Andhra Pradesh, India, report in a paper that has recently been published in the International Journal of Recent Trends in Science And Technology (Shruthi. 2013).

31" waist as a starting value? Obviously not a US study*

Ramadan fasting increases fatty acid oxidation: In 1995 Jalila El Ati and her colleagues were able to show that the respiratory quotient, i.e. the ratio of carbs / fats that are being burned as fuel decreases by ~10% in healthy 25-39 year old women (El Ati. 1995).

The study was conducted at the research lab of Department of Physiology Bhaskar Medical College during the month of Ramadan in the year 2011 (Aug - Sept). The subjects were 50 young adults in the age group 18-24yrs - with 6 dropouts (personal reasons) that leaves us with data on the changes in body composition, blood pressure, and heart rate from 44 subjects, whose baseline BMI (24kg/m²) was very different from that of the "average" American and whose 31.5" waist is a clear indicator that they were in pretty good shape (compared to those who are currently totally digging alternate day fasting after they have failed with the South Beach, the Weight Watchers and the rest of the "I am a stupid lazy ass and don't want to make the appropriate lifestyle changes" diets in the past.

* Health alarm: Did you know that the average US teenager had a 34" waist, in 2004? That was already 2" more than 5 years before (Li. 2006; data based on NHANES 2004). If we extrapolate a yearly increase of 0.25"  this means we should have arrived at 35.25" today.

You will often hear the proponents of the the idea that some people are simply "naturally lean" state that this is usually a result of the fact that they are eating "frequent small meals" to satiety. So, based on that argumentation you would actually expect that the subjects in the study at hand, who would probably qualify as "naturally lean", may have jeopardized this "natural leanness" by robbing themselves of the opportunity to keep "grazing".

Figure 1: BMI, waist and hip circumference and body fat % before and after 28 days Ramadan fasting (Shruti. 2013)

As the data in figure 1 goes to show you this obviously did not hurt the results of the 44 subjects in the study at hand, who lost an everage of 3.1% body fat within 28 days. Given the fact that all the initially mentioned factors should reduce the efficacy of Ramadan fasting for improvement in body composition compared to that of a fast in the (meanwhile) classic "lean gains" style, this appears pretty damn impressive, right?

If you take into account that the scientists measured only subcutaneous fat (this is a necessary result of using the skinfold method), which is usually comparably slow to respond, it certainly argues for the cosmetic advantage of timed feasting over uncontrolled all-day snacking - whether the same would yet be true if we standardized the caloric and macronutrient intake is questionable (see my comment on the 2-day a week fast in the box below, as well).

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Why do the fast 2x per week diets work? It's easy the main working principle is a reduction in calorie intake. If you assume you have a 2,400kcal intake and cut back to 800kcal (some prescribe 500kcal) on 2 days that's a 66% (80%) reduction in energy intake. Interestingly, though the compensation effect is much less pronounced than you would expect and occurs usually only on the days after the fast. So, 10% more on the days after the fasting days leaves us with a caloric deficit that will still amount to 2.720kcal (3320kcal for the 500kcal variety) or 10% (20%) per day.

Impressive it is, but in the end it's still basic mathematics: As impressive as it may be, the underlying reason - and this is something all previous Ramadan studies appear to support a simple reduction in energy intake that is, at least in some cases, supported by improvements in diet quality, reductions in carbohydrate and increases in protein intake that are brought about by the elaborate cooking, the absence of snacks and sugar sweetened beverages and the mere fact that you simply cannot stomach the same amount of food you would usually consume in three main meals and two snacks within one or two meals... no matter how huge those meals may be.

Does that exclude that "having AMPK come to its right", sirtuins, increased fatty acid oxidation and the whole fastin' hoopla may figure here, as well? No it does not, but even the significant reduction in systolic and diastolic blood pressure in the study at hand, as well as the improvements in glycemia and lipid metabolism in previous Ramadan studies are, when all is said and done, eventually brought about by the downstream effects of a reduced calorie intake. And this, is by the way also true for the "eat whatever you want all week long and cut back to 800kcal (or 500kcal) mainly from protein on two out of seven days" diets as well (see infobox to the right for an example calculation).

References:

• el Ati J, Beji C, Danguir J. Increased fat oxidation during Ramadan fasting in healthy women: an adaptative mechanism for body-weight maintenance. Am J Clin Nutr. 1995 Aug;62(2):302-7. 
• Li C, Ford ES, Mokdad AH, Cook S. Recent trends in waist circumference and waist-height ratio among US children and adolescents. Pediatrics. 2006 Nov;118(5):e1390-8.
• Shruthi B, Hassan A, Reddy BV. The Effect of Ramadan Fasting on the Body Composition, Blood Pressure, Heart Rate of Healthy Young Adults. International Journal of Recent Trends in Science And Technology, ISSN 2277-2812 E-ISSN 2249-8109, Volume 8, Issue 1, 2013 pp 31-35.

Orange Juice to Battle Cancer? Is There Anything to the Recent Mainstream Media News? Plus: How Much of The "Good Stuff" Is Lost Upon Pasteurization?

I am sorry, but if you still believe this was a healthy breakfast, I am not sure you will be able to escape diabesity ;-)

You may have read it on one of the major Science News Portals, on Saturday: "[Orange juice] could contribute to chemoprevention at every stage of cancer initiation and progression. Among the most relevant biological effects of OJ [orange juice] is the juice's antigenotoxic and antimutagenic potential, which was shown in cells in culture and in rodents and humans." (Taylor & Francis. Press Release from 13. September 2013).

Really? And what about the >20% increased diabetes risk from drinking fruit juices (Muraki. 2013)?

If that's what you have just been thinking, I bet you will like to get some more information about the hesperidine and naringenine content of orange juice and how these could influence cancer development.

Three epidemiological studies! Really?

It does not take much these days to turn hopes into hypes - for orange juice it appears at first sight as if three studies were enough. If you look closer at the image that emerges whence you read the information Rech Franke et al. provide in a tabular overview in their paper you it does however turn out that their "evidence" is actually refuting their own argument:

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  Don't worry if you have not heard of Polypodium leucotomos before. After all, that's why you're here! To get your daily dose of SuppVersity news and learn, right? So, if you want to know about it's beneficial effects on the immune system of athletes like yourself and how it can protect your skin from damage, by UV radiation, surf back to the SuppVersity news from Oktober 2012 | go there!

  Drinking orange juice is associated with increased skin cancer risk: A population-based case-control study evaluating the relationship between citrus consumption and the history of squamous cell carcinoma of the skin in an elder Southwestern U.S. population (n=242 cases and 228 controls) that found that there was no association of OJ consumption and reduced risk of developing skin cancer, but a highly significant -34% risk reduction for those who are too lazy to get rid of the citrus peel (Hakim. 2000).
• Vitamin rich foods in general are cancer-protective, but orange juice is not: A follow-up study conducted with data from two Nurses' Health Study cohorts found a relationship between vitamins and certain foods and the risk of melanoma, orange juice, however was not among those foods. In fact, the more OJ the subjects were drinking the higher was their risk of developing skin cancer (Feskanich. 2003)

Ok, I got to be fair, there is a third human study, where OJ does actually appear to to the trick - it's not skin cancer, but leukenia, but still:

• Early life OJ consumption is linked to lower leukemia risk: A case-control study by Kwan et al. aiming to study the relation between child’s early diet and risk of childhood leukemia in diverse California population (n=328 case-control sets) observed that the regular consumption of orange juice before the age of 2 years was associated with a -46% reduction in risk of childhood leukemia diagnosed between the ages of 2 and 14 yr (Kwan. 2004)

Now, aside from the fact that we are obviously talking about different forms of cancer, it should be obvious that you are picking only the best orange juice for your toddler and won't feed him or her the same junk you are probably going to buy for your Tequila Sunrise ;-)

Is OJ quality the critical factor?

If you are a regular, here at the SuppVersity you will probably already be guessing, where this is heading: Towards a quality, not a quantity discussion. We all do after all know that citrus fruits with their thick skin are the #1 favorite target for the spray on pesticides (Lu. 2005)

Figure 1: Loss of selected total and individual flavanones, flavones, and hydroxycinnamic acid derivatives (all healthy secondary plant products) after standard pulp pasteurization of commercial OJ (Gil-Izquierdo. 2002)

Doesn't matter? Who eats the peel anyway... Oh, yes you are right. The only problem with this logic is that if you don't eat the peel or at least the white bitter stuff that's right in-between the peel and the fruit, you don't get the full load of phenols and will hardly see any of the benefits the companies selling commercial "orange juice" (not so sure there are oranges in this stuff, anyway) claim their products would have.

If you go hardcore, though, and simply "juice" the whole fruit, on the other hand, you will not just increase the amount of allegedly healthy secondary plant products. You will also maximize the amount of pesticides you ingest and the truckloads of sugar you will need to make the bitter brew palatable. If we do now also take into consideration that Lu et al. report that even "organic" orange juice from oranges where 99% of the peel has been removed has pesticides in it, it may, after all, still be a quantitative issue, where minimizing your intake of orange juice and eating the occasional organically grown orange would be your best bet to cheat death by "healthy juices" ;-)

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Conventional vs. organic? All bullocks or is it worth paying more (learn more)

Bottom line: So, what does the real-world check tell us about the "benefits" of orange juice? Right, it's neither laden with hesperitin nor narengenin, because those are in the part of the fruit we throw away because it is (a) laden with pesticides and (b) so bitter that even the tons of sugar we currently add to the commercial orange juices will not make it tasty.

So, what do we do with b***s*** mainstream science news like these? File them next to the "eating chocolate will turn you into a Nobel laureate" news that even made it to CNN and co, when the pertinent study Messerli was published in 2012. What folder that would be? Well it's the "for those who are stupid enough to believe everything they read folder" ;-)

References:

• Feskanich D, Willett WC, Hunter DJ, and Colditz GA: Dietary intakes of vitamins A, C, and E and risk of melanoma in two cohorts of women. Br J Cancer. 2003; 88:1381–1387.
• Gil-Izquierdo A, Gil MI, Ferreres F. Effect of processing techniques at industrial scale on orange juice antioxidant and beneficial health compounds. J Agric Food Chem. 2002 Aug 28;50(18):5107-14.
• Hakim IA, Harris RB, and Ritenbaugh C: Citrus peel use is associated with reduced risk of squamous cell carcinoma of the skin. Nutr Cancer. 2000; 37:161–168.
• Kwan ML, Block G, Selvin S, Month S, and Buffler PA: Food consumption by children and the risk of childhood acute leukemia.Am J Epidemiol. 2004; 160:1098–1107.
• Lu C, Bravo R, Caltabiano LM, Irish RM, Weerasekera G, Barr DB. The presence of dialkylphosphates in fresh fruit juices: implication for organophosphorus pesticide exposure and risk assessments. J Toxicol Environ Health A. 2005 Feb 13;68(3):209-27.
• Messerli FH. Chocolate consumption, cognitive function, and Nobel laureates. N Engl J Med. 2012 Oct 18;367(16):1562-4.
• Muraki I, Imamura F, Manson JE, Hu FB, Willett WC, van Dam RM, Sun Q. Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies. BMJ. 2013 Aug 28;347:f5001.
• Rech Franke SI, Guecheva TN, Henriques JA, Prá D. Orange Juice and Cancer Chemoprevention. Nutr Cancer. 2013 Aug 6. [Epub ahead of print]

T-Gel with or Without an Aromatase Inhibitor? If You Are Healthy & Lean and Want to Stay This Way, There is Only One Answer: T-Gel Without Aromatase Inhibitor!

Don't let her talk you into participating in studies that risk your manliness ;-)

Would you be willing to participate in a study, where you could end up without testosterone? No? Well me neither... strangely Joel S. Finkelstein et al. were able to find 198 healthy men between 20 and 50 years who were stupid enough to participate in an experiment, where they were randomized to placebo, or testosterone gel (1.25, 2.5, 5, or 10g per day) while being on gosererelin acetate, which did suppress their natural testosterone production.

With additional 202 subjects receiving an identical "treatment", but in this case alongside a whoppy dose of the aromatase inhibitor anastrazol as a bonus, the study design leaves us with plenty of groups and tons of subjects. To "determine the relative degree of testosterone deficiency, estradiol defi­ciency, or both at which undesirable changes in body composition, strength, and sexual function begin to occur." (Finkelstein 2013)

Yep, that is the study you don't not want to be part of, but....

I bet you will still be interested in the results. Am I right? Ok, let's see then. In men receiving goserelin acetate (kills the natural testosterone production) and 0 g (pla­cebo), 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily (cohort 1), the mean testosterone levels were

• 0g testosterone: 44±13 ng per deciliter, 
• 1.25g testosterone: 191±78 ng per deci­liter
• 2.5g testosterone: 337±173 ng per deciliter, 
• 5g testosterone 470±201 ng per, and
• 10g testosterone 805±355 ng per deciliter

With 1.4 pg per milliliter, 7.9±2.9 pg per mil­liliter, 11.9±5.7 pg per milliliter, 18.2±10.2 pg per milliliter, and 33.3±15.3 pg per milliliter the estrogen levels of all participants were all well within the normal range (<55pg/ml).

Update: As Dr. Crisler (www.allthingsmale.com) just told me the accuracy of the information about estrogen may be questionable, because the essay the scientists used is not reliable in adult men. Instead, he suggest you use a "sensitive" essay like LabCorp (#500108), which uses the "cutting edge" LC/MS technology, Mayo Clinic's "Enhanced Estradiol" (#81816) or LabCorp's "Sensitive Estradiol (#140244), which is less expensive and thus probably a good choice for those without insurance. Dr. Crisler also pointed out that the wide variations you see in T-levels are actually a "very good thing, since this more closely mimics the serum profile of young healthy men". I do not deny that, but I still thought that it was wise to point out that the difference between 805ng/dl and 924ng/dl is absolutely non-significant when you have a range of ±521ng/dl.

Now the latter was obviously true for the guys on the aromatase inhibitor as well, with 1-2pg/ml their levels were however pathologically low and considering the high standard deviations, their T-levels were not that much higher:

Figure 1: Testosterone (ng/dl) and estrogen (pg/ml x10) in healthy men on 0, 1.25, 2.5, 5 and 10g (T0-T10) of testosterone gel with and without an additional aromatase inhibitor (Finkelstein. 2013)

"In men who also received anastrozole (cohort 2), the corresponding mean testosterone levels were 41±13 ng per deciliter, 231±171 ng per deciliter, 367±248 ng per deciliter, 485±240 ng per deci­liter, and 924±521 ng per deciliter and the corresponding mean estradiol levels were 1.0±0.4 pg per milliliter, 1.2±0.4 pg per milliliter, 2.0±2.3 pg per milliliter, 2.1±1.9 pg per millili­ter, and 2.8±1.8 pg per milliliter." (Finkelstein 2003)

[*please note the high (up to 50%!) standard deviations which tell you that the response to transdermal testosterone may vary profoundly from one men to another]

If you take a closer look at the data in Figure 1 and keep in mind that I had to multiply the estrogen levels by x10 in order to fit them into the same graph, it becomes all the more evident that the men in the non-AI group all had normal (<55pg/ml) estrogen levels. Their peers in the anastrazole group, on the other hand, had basically no estrogen at all and correspondingly high testosterone to estrogen ratios. In the worst case (yep, that is something bad!), namely 10g of t-gel + A,I the latter was as high as 335, which is almost 12x higher than in the 2.5g testosterone group without anastrazole (cohort 1).

No T, but tons of body fat

Apropos, cohort 1, in this group of men those who received the anti-androgen goserelin alongside a low(ish) doses of T-gel, i.e. either 0 g, 1.25 g, or 2.5 g of testosterone, daily, had significantly higher body fat levels and those in the 0 and 1.25g of T-gel significantly lower levels of lean mass compared to their peers in the 5g T-gel per day group.

Just a reminder: The testosterone level of the guys in the 5g group was only 470ng/dl and thus still rock bottom - the age adjusted normal levels for men are after all (I highlighted the group, where most of the subjects were in):

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  Effects of high and low testosterone on body composition (learn more)

  14-15 yr: 33-585 ng/dL
• 16-17 yr: 185-886 ng/dL
• 18-39 yr: 400-1080 ng/dL
• 40-59 yr: 350-890 ng/dL
• > 60 yr: 350-720 ng/dL

Those on the highest dose of T-gel (10g) ended up at the top (remember the standard deviations) of the normal range for testosterone and right in the happy medium for estrogen (normal range is 14-55pg/ml). These guys  experienced a significant decrease in body fat and increases in tigh muscle area and leg press strength.

Interestingly, both the decrease and increase in body in response to high and low testosterone levels occurred almost exclusively in the "benign" subcutaneous adipose tissue. The intra-abdominal­ fat area, on the other hand did not change significantly in any group. If we follow the standard interpretation of the health effects of the different body fat stores, the conclusion would thus be that low T is not so much of a problem, after all it's all "healthy fat" that you will gain... to bad that too much of that "healthy fat" will make you just as insulin resistance as the visceral fat - it just takes longer for the negative effects to occur.

Now what did the AI do?

Suggested read explaining why the annihilation of E2 has negative effects on your body comp: "Estrogen, Friend or Foe of Muscle Hypertrophy? Plus: Are You 'SERMing' Away Your Satellite Cells?" | more

I know, the most intriguing question has not been answered yet: What was the role of anastrazole in all this? And how did the subjects in cohort 2 fare compared to their "high" (remember even the 10g guys had normal estrogen levels) estrogen counterparts. Well,...

"In cohort 2, the percentage of body fat increased in all groups when the aromatization of testosterone to estradiol was inhibited. The magni­tudes of these increases were similar with doses of 0 g, 1.25 g, 2.5 g, and 5 g of testosterone daily, a finding that suggests a predominantly estro­genic effect" (Finkelstein. 2013)

Yep, I deliberately quoted this, because I know that you've been brain-washed to believe the opposite would happen. The big bad estrogen is what keeps you lean... good that you have been taking natural AIs for years, right? Well, no obviously not. Probably rather the reason that you still don't have the cover-model look you are aspiring.

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Did you know that (a) the endogenous production of estrogens has significant protective effects on your heard cardiovascular health (Sudhir. 1999) and that (b) aromatase is neuroprotective and low levels of it have been associated with the occurance + progression of neurological diseases such as dementia, Alzheimer's and Parkinsons as well as an inability to recover from mechanic (trauma) or chemical (intlammation) damage to the brain (Azcoitia. 2001)? No? Well, let's hope that this is because you've never heard it and not because you've been abusing AIs for the past decade ;-)

So, to use an AI or not - is that even a question? A direct comparison of all the data from cohort 1 (no aromatase inhibitor) and cohort 2 (using anastrazole), informs us that

"The cohort–testosterone dose interaction was significant for the percentage of body fat (P = 0.001), intraabdominal­fat area (P = 0.021), subcutaneous ­fat area (P = 0.029), sexual desire (P = 0.045), and erectile function (P = 0.032)" (Finkelstein. 2013)

Or, to put it another way: The study shows us that estradiol exerts an inde­pendent effect on body fat, sexual desire and erectile function. So you better don't ignore the real world implications you are about to suffer, when you put too much faith in hearsay instead of looking at your actual blood levels:

"In the groups that received testosterone, inhibi­tion of estrogen synthesis (cohort 2), as com­pared with intact estrogen synthesis (cohort 1), was associated with significant increases in the percentage of body fat (P<0.001), subcutaneous­ fat area (P<0.001), and intraabdominal­fat area (P = 0.002) and with significant decreases in sexual desire (P<0.001) and erectile function (P = 0.022)" (Finkelstein. 2013)

Yes, you heard the scientists right. Suppressing your estrogen levels is going to make you fat, rob you of your sexual desire and render you unable to perform the deed.

At the same time it had no beneficial effect on the increases in lean body mass or strength or any other positive outcome the subjects got from using T-gel. On the contrary, the low estrogen levels on in the 10g T-gel group did actually blunt reduce the lean mass gains and the fat loss the men in cohort 1 (no anastrozole) experienced, when they used 10g of T-gel per day was effectively reversed by the AI.

Figure 2: Fat gain, lower lean mass gain, less sexual desire & lower sexual function (not shown) and the list goes on... there really is nothing remotely beneficial about low estrogen (figures from Finkelstein. 2013).

It should thus be absolutely obvious that the only reason you should use an aromatase inhibitor with your testosterone replacement therapy is blood work that indicates that you have serious issues with over-aromatization. In many cases those can be reduced if not solved by (a) reducing inflammation and (b) getting rid of your belly.

To deliberately annihilate your estrogen levels, on the other hand, is simply stupid - irrespective of whether you are on TRT or not and even if you don't care about the negative long-term effects on your brain and heart health.

References:

• Azcoitia I, Sierra A, Veiga S, Honda S, Harada N, Garcia-Segura LM. Brain aromatase is neuroprotective. J Neurobiol. 2001 Jun 15;47(4):318-29.
• Sudhir K, Komesaroff PA. Clinical review 110: Cardiovascular actions of estrogens in men. J Clin Endocrinol Metab. 1999 Oct;84(10):3411-5. Review.

Liver Enzymes the #1 Marker of Insulin Resistance!? What Do HbA1C & ALT, AST and GPT Tell Us About Diabesity?

Just like type II diabetes, NAFLD is a life-style disease.

While it may not be obvious, today's SuppVersity post is very closely related to Sunday's post about supplements to battle insulin resistance. The recent revelation that the liver enzymes alanine transaminase (ALT aka GPT), aspartate transaminase (AST aka SGOT) and gamma-glutamyl transpeptidase (GGT aka gamma-GT) and not free fatty acid levels are the most reliable predictors of insulin sensitivity in overweight and obese, non-diabetic adults does after all show clearly support the notion that we (scientists, doctors, patiens) should pay much more attention to the liver. It's the liver that controls blood glucose, lipids and even our hormone levels, not the adipose organ. Therefore it is in the liver, our metabolic organ #1, is where the dark diabesity magic happens.

Heal the liver, cure the insulin resistance

Just in: A recent Stanford study shows that the use of VEGF inhibitors that are usually prescribed as cancer drugs can help diabetics manage their blood glucose levels, by increasing the expression of a protein (HIF-2alpha) that's usually expressed in response to hypoxic cell death and will - as a side effect - increase the expression of insulin receptors and thus restore hepatic insulin sensitivity and the optimal function of all the regularory processes that depend on it (Conger. 2013).

Usually you will think of being overweight and undermuscled, of insulin resistant myocytes (muscle cells) and adipocytes (fat cells) and about eating too much simple sugars, whenever someone is talking about the etiology of insulin resistsance. NAFLD, i.e. non-alcoholic fatty liver disease, on the other hand, is still often thought of as one of the long-term side effects of T2DM.

A recent study from the Children's Nutrition Research Centre at the University of Queensland does however suggest that the connection between having a messed up liver and being insulin resistant does not just start much earlier, than previously thought, but is probably also directly involved in the progression from being slightly insulin resistant to being a real diabetic.

Certainly, central adiposity (=high amounts of visceral, inter-organ fat) is and will always be one of the key risk factors for the development of insulin resistance and its progression towards full blown type 2 diabetes. Whether this is mainly a function of the spatial proximity of the constantly inflamed visceral fat depot to the liver is still a matter of current research. What we do know already is however that the presence of NAFLD is an independent risk factor for cancer and heart disease (Guebre-Egziabher. 2013)

Once the liver has taken a beating, the downstream effects are profound

One thing that's for sure, though, is that the downstream effect that occur, whence the liver is beginning to take a hit are profound:

• endocrine imbalances resulting from errors in the cytochrome enzymatic cascade that's responsible (among other things) for the conversion and clearance of all sorts of hormones
• messed up cholesterol levels and lipid profile with increases in LDL and VLDL lipoproteins and decreases in HDL
• chronically elevated  glucose levels due to lowered glycogen storage capabilities and a lack of control of the gluconeogenic processes in the liver that are no longer shut off when insulin is present, 
• increased fatique that's mediated at least in parts by the accumulation and build-up of toxic metabolic byproducts and environmental toxins the liver cannot handle any longer

The list goes on and on and I bet you that all 40 overweight and obese (body mass index≥25.0kg/m²) subjects with elevated ALT and AST values in the study at hand were already suffering from these problems.

Figure 1: Correltion coefficients for blood glucose, blood insulin and HbA1C (Gray. 2013)

No wonder that the data in Figure 1 confirms that there is no other parameter - including BMI, adiponectin, blood lipids, i.e. LDL, HDL, etc., I-CAM or ghrelin (the latter are not shown in the figure) that come remotely close as far as their reliability as markers of insulin resistance and the corresponding elevations of the long-term glucose marker HbA1C are concerned.

This does also mean that the study at hand would refute the results of previous experiments which suggest that the mobilization of FFA in the circulation promotes insulin resistance, however

Please remember: AST, ALT & CK will be elevated after workouts so take a couple of days off before you get blood work done.

"this [particular] study found no direct correlations between FFA and markers of insulin sensitivity. Furthermore, there were no clear correlations between markers of insulin sensitivity (glucose, insulin, HbA1C, or HOMA scores) and physical activity or self-reported fatigue. Fatigue scores were correlated with C-reactive protein, suggesting that inflammation may play a role, although there was no significant correlation with ICAM-1"(Gray. 2013)

Overall the currently data from the Gray study does therefore clearly support the notion that there is a  direct "link between liver function, adiposity, and the development of IR [insulin resistance]" (Gray. 2013) that goes well beyond the common understanding of 'adiposity begets insulin resistance, insulin resistance triggers NAFLD'.

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Figure 2: Liver tissue in rodents fed a hypercaloric high sucrose diet with (B) and w/out (A) taurine.  Taurine inhibited the development of hepatic steatosis (Gentile. 2011)

Bottom line: While the results of the study at hand certainly shift the focus away from the fat cells and towards the liver, they do not change the fact that "insulin resistance and the subsequent development of T2DM remain primarily lifestyle disorders" (Gray. 2013). In other words, if you followed all the "non-quick fix" tips from part I of the "Restore & Keep Insulin Sensitivity" series, in the first place - you would not have to worry about insulin resistance or non-alcoholic fatty liver disease (NAFLD).

Still, with a new emphasis on the involvement of the liver, the way we approach insulin resistance with supplements may in fact change... Although, when you come to think about it two of the top-supplements from the first and second serving of insulin sensitizing supplements, you will realize that many of them (e.g. alpha lipoic acid, taurine, berberine, etc.) are also known "liver protectors" (Gentile. 2011; Valdecantos. 2012).

Similar data on both improvements in liver health and insulin sensitivity is available for NAC (Haber. 2003) and milk thistle (Maghrani. 2004), as well. It is thus not too far off to assume that whatever you do to protect your liver is also going to have beneficial effects on your glucose metabolism; and what's even better it will improve your blood lipids, make your that your endocrine system works optimally, protect you against the constant assault of environmental toxins and reduce your chance of being carried off by diabetes, cancer and heart disease... still not convinced? Well, then think about something my good friend Carl Lanore likes to say "liver has the words 'to live' or 'life'" in it ;-)

References:

• Gentile CL, Nivala AM, Gonzales JC, Pfaffenbach KT, Wang D, Wei Y, Jiang H, Orlicky DJ, Petersen DR, Pagliassotti MJ, Maclean KN. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1710-22.
• Gray B, et al., Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, nondiabetic adults, Nutr Res. 2013 [published ahead of print]
• Guebre-Egziabher F, Alix PM, Koppe L, Pelletier CC, Kalbacher E, Fouque D, Soulage CO. Ectopic lipid accumulation: A potential cause for metabolic disturbances and a contributor to the alteration of kidney function. Biochimie. 2013 Jul 27.
• Haber CA, Lam TK, Yu Z, Gupta N, Goh T, Bogdanovic E, Giacca A, Fantus IG. N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E744-53. Epub 2003 Jun 10.
• Maghrani M, Zeggwagh NA, Lemhadri A, El Amraoui M, Michel JB, Eddouks M. Study of the hypoglycaemic activity of Fraxinus excelsior and Silybum marianum in an animal model of type 1 diabetes mellitus. J Ethnopharmacol. 2004 Apr;91(2-3):309-16.
• Conger K. Approved cancer drug potentially could help treat diabetes, researchers find. <http://med.stanford.edu/ism/2013/september/diabetes.html> retrieved September 16, 2013.
• Valdecantos MP, Pérez-Matute P, González-Muniesa P, Prieto-Hontoria PL, Moreno-Aliaga MJ, Martínez JA. Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3. Obesity (Silver Spring). 2012 Oct;20(10):1974-83.

Dietary Fructose vs. Endogenous Fructose Production: Is The Aldose Reductase Mediated Production of Fructose to Blame for Diabesity & NAFLD? Plus: Could Amla Help?

Make you choice - cholesterol and regular sugar (left), or fat free and fructose-laden? In the end it all may not even matter.

When I stumbled upon a recent study from the University of Colorado a few days ago, my first thought was: Oh my! That sounds familiar. And indeed, if you know anything about the "cholesterol conundrum" you will probably feel reminded of the disconnect between cholesterol intake, cholesterol levels in the blood and cholesterol-related increases in cardiovascular disease risk - don't forget that this is still an issue, although it may neither be your dietary cholesterol or your total cholesterol levels that mediate the risk increases.

Looks like you cannot pick your poison, because whatever you chose, your body will produce what it considers fitting from it

According to the said study from the University of Colorado it does in fact seem that our current favorite villain, namely fructose, has more in common with its predecessor on the throne of "avoid at all costs nutritional evils", i.e. cholesterol, than we have previously thought.

Surprise! Some of you may have heard about it for the first time 8 days ago in the first serving of insulin-sensitizing supplements, here at the SuppVersity: Amla aka Emblica officinalis is a natural aldose reductase inhibitor (Pupalla. 2012) and would thus be qualified to keep the negative side effects of endogenous fructose production in check!

"Many high glycaemic foods also contain fructose. For instance, sucrose is a disaccharide of glucose and fructose, and high-fructose corn syrup is a mixture of glucose and fructose, raising the question of whether fructose is responsible for the effects of high glycaemic foods to increase the risk for metabolic syndrome. To further complicate this issue, fructose can be generated endogenously via the polyol pathway from glucose. Specifically, aldose reductase (AR) metabolizes glucose to sorbitol, which can then be converted to fructose by sorbitol dehydrogenase.

Thus, if AR were highly expressed or activated in the liver, some of the glucose absorbed might be converted to fructose, and hence possibly provide a mechanism for inducing features of the metabolic syndrome."

To render this a little more straight forward, let's get back to our cholesterol analogy: We know (or should know) that part of the reason that dietary cholesterol is not a danger / problem for us is a simple consequence of the fact that most of the cholesterol that's floating around in our blood is actually produced directly within our bodies. And for cholesterol the rule of thumb is: The less cholesterol we eat, the more we will be producing ourselves.

Do we sugar- / fruit-coat ourselves?

For fructose this should actually be different. After all, fructose is not of similar physiologic importance to us as cholesterol the "fatty acid shuttle" and steroid precursor. Still, necessary or not, at least the results of the study at hand appear to suggest that the mammalian body appears to like his fructose so much that it will just produce it on its own, even when the diet is fructose free.

Unforuntately, the consequences Lenaspa et al. observed, when they kept 4 groups of rodents (wild-type and fructokinase knockout (KO) mice, who cannot produce fructose from glucose) on diets with or without glucose (10% (wt/vol)) in the drinking water and compared the body compositional changes of these mice to a control group pm regular chow (containing 60% carbohydrate and no fructose), appear to suggest that this is exactly as bad as guzzling fructose corn syrup all day.

Figure 1 : When the aldose reductase enzyme is deactivated mice will gain significantly less weight and avoid both insulin resistance and NAFLD despite being on a high glucose (no sugar) diet (Lanaspa. 2013)

In fact, the absence of the enzymes that are necessary to do the conversion of glucose to fructose did not just lead to a major and significant reduction in weight gain, it also blunted the typical pro-non-fatty liver disease effects of high sugar diets and kept the insulin sensitivity of the knockout mice in the glucose group in check.

Figure 2: Fructose uptake (mmol/g tissue per min) increases with glucose concentration (mmol/L; Uhsijima. 1995)

"These studies suggest that under certain conditions glucose may induce metabolic syndrome in mice via an AR [=fructose production via aldose reductase], fructose-dependent pathway. Whether this is occurring in humans ingesting high glycaemic foods remains to be determined. However, as in mice, AR can be activated in humans by a number of ways, including by high glucose concentrations. Total parenteral nutrition, in which a 35% glucose solution is provided
by the vein, is associated with the development of fatty liver, andexperimental studies have shown that it is mediated by the glucose component of the infused fluids

Soft drinks containing high-fructose corn syrup also deliver markedly high-glucose solutions (4–6%) to the gut, and sucrose-containing soft drinks provide similar amounts of glucose after the sucrose is degraded in the intestine." (Lanaspa. 2013)

With these new results it becomes even more obvious why HFCS which is actually a mixture of glucose and fructose is particularly nasty. It will not only increase the absorption of fructose (see Figure 2), but also provide our bodies with the necessary substrate to top an already overabundant fructose intake off with endogenously fructose to create something even I, as an outspoken critic of the "fructose hypothesis of obesity" would say is part of the perfect obesogenic storm and could easily explain why soft drink intake is so closely associated with an increased risk for obesity, fatty liver and insulin resistance.

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Suggested read on the never-ending debate on the "fundamental difference" between glucose and fructose: "Glucose vs. Fructose and Their Effects on Glucose, Insulin & Fat Oxidation" | read more

Bottom line: No, the study at hand does not imply that HFCS is harmless (on the contrary it adds another reason it's poison), but it should remind all of us that an exuberant (but not an appropriate) glucose intake is not necessarily causing less damage than fructose. Consumed in high enough amounts it's going to set the fructose production machinery of our body in gear and will thus yield very similar metabolic problems as fructose itself, the current scape-goat for "all things metabolic syndrome".

If you want to make absolute sure you really mess yourself up, I do however strongly advice you add some saturated fats, preferentially palmitic acid, to maximize insulin resistance and make sure the glucose cannot be taken up by your muscle before it can either harm you directly, or after being converted to fuctose or triglycerides.

What? Oh yeah, you're right! That's what 90% of our fellow Westerners do. Eating a high fat, high carb diet and sitting around all day... well, I guess it's thus not the fructose from the one apple they consume per months that's to blame for their misery, is it?

References:  

• Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzicky P, Rivard C, Inaba S, Roncal-Jimenez CA, Bales ES, Diggle CP, Asipu A, Petrash JM, Kosugi T, Maruyama S, Sanchez-Lozada LG, McManaman JL, Bonthron DT, Sautin YY, Johnson RJ. Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun. 2013 Sep 11;4:2434.
• Puppala M, Ponder J, Suryanarayana P, Reddy GB, Petrash JM, LaBarbera DV. The isolation and characterization of β-glucogallin as a novel aldose reductase inhibitor from Emblica officinalis. PLoS One. 2012;7(4):e31399.
• Ushijima K, Riby JE, Fujisawa T, Kretchmer N. Absorption of fructose by isolated small intestine of rats is via a specific saturable carrier in the absence of glucose and by the disaccharidase-related transport system in the presence of glucose. J Nutr. 1995 Aug;125(8):2156-64.