Are You Afraid that the Fructose Boogieman Clogs Up Your Liver? Citrulline or Alanine, Glycine, Proline, Histidine and Aspartate Mix Will Protect You + Maybe Lean You Out

If you belong to the people who simply cannot stay away from HFCS foods and beverages, you may be happy to hear that the equivalent of as little as 10g citrulline or NEAAs in your diet may do much more than "just" fully prevent its negative effects on your liver.

You will probably remember from previous articles I wrote that NAFLD, or rather the development of non-alcoholic fatty liver disease, is one of the earliest markers of metabolic syndrome and beginning type II diabetes. In the Western obesity societies in North America and Europe, NAFLD is among the most common causes of chronic liver disease and its prevalence is increasing rampantly (Marchesini. 2001).

In spite of the fact that its development is most strongly linked to the consumption of a generally unhealthy, energetically dense diet, there are several lines of evidence which suggest that the ingestion of exorbitant amounts of fast-digesting fructose from high fructose corn syrup (HFCS) sweetened beverages or processed foods is one, if not the most reliable motor of its development (Volynets. 2012).

You can learn more about citrulline at the SuppVersity

Citrulline prevents muscle catablism more than leucine

Arginine & citrulline for blood lipid control

EAA, BCAA, or citrulline for anti-catabolism?

Glutamine not citrulline to heal the gut?

Citrulline to ignite fatty acid oxidataion?

High & low dose arginine ineffec- tive NO boosters

On a molecular level fructose has been shown to trigger the production of fat from glucose in the liver (de novo lipogenesis | DNL). It does so by activating certain enzymes via the sterol regulatory element binding protein-1c (SREBP1c) and/or the carbohydrate-responsive element-binding protein (ChREBP). In conjunction with the corollary hepatic oxidative stress and the subsequent increase in insulin resistance, the onslaught of readily absorbed fructose from processed foods and HFCS-sweetened beverages is thus  like gasoline on the fire of the obesogenic baseline diet some people refer to as the "standard american diet" (learn why the "SAD-diet" is so good at making you fat). On the whole, however, the accumulation of fatty streaks in the liver that's so characteristic of NAFLD is yet only the point of departure of the journey to the land of the super-obese type II diabetics.


Now this journey from slightly overweight to super-obese is a journey of which many previous studies studies already suggested that it could take a very different route if people consumed higher amounts of protein and/or certain amino acids (AAs):

• Theytaz et al. (2012), for example, found a "liver cleansing" increase in VLDL-TG release by the liver with an essential AA-enriched diet, and
• Bortolotti et al. (2012) showed that a protein-enriched diet can effectively reduce the fructose induced lipid accumulation in the liver through increased energy expenditure. 

As Prasanthi Jegatheesan et al. point out, "[t]hese beneficial effects of AAs or proteins may arise through lipid oxidation, decreased DNL, and modulation of genes involved in lipid metabolism" (Jegatheesan. 2015). Since citrulline is the precursor for the renal synthesis of Arg, which is known to improve insulin sensitivity and lipid metabolism, and has been shown to have beneficial effects on the level of plasma triglycerides and fat deposition in the liver, the authors of a recent study speculated that "Cit supplementations might [...] able to limit the development of fructose-induced NAFLD" (Jegatheesan. 2015). Morever, Jegatheesan et al. expected to see similar effects with other nonessential amino acids (NEAA), of which their own previous research had shown that they may offer similar anti-NAFLD effects.

Where's the control group? Previous studies show that diets which are supplemented with NEAAs (alanine, glycine, proline, aspartate, histidine, and serine) or citrulline have metabolic and nutritional effects similar to a regular control diet, alone (Osowska. 2006; Jegatheesan. 2015). The CNEAA group is thus the "control" group in the study at hand. That's "ok" and doesn't make the study results useless, but in view of the fact that the data in Figure 2 shows more than just an ameliorative effect of citrulline on NAFLD, I would have preferred a regular control group in which the rodents had been fed standard chow without added non-essential amino acids.

To confirm or falsify their hypotheses, the researchers randomized twenty-two rats into four groups on different diets:

• CNEAA as in control - control diet without added fructose + 1g/kg non-essential amino acids (for humans that's roughly 11g per day | this was the control diet in the study at hand)
• F as in fructose- control diet enriched with 60% fructose without supplements
• FNEAA as in control + fructose - fructose enriched diet (F) + 1g/kg non-essential amino acids (which happens to be the control diet in the study at hand)
• FCIT as in fructose + citrulline - fructose enriched diet (F) + 1g/kg citrulline

In that, it's important to note that the NEAA supplement contained isomolar amounts of the 6 AAs and was isonitrogenous to the Cit diet. So, a mere difference in the nitrogen content of the chow cannot explain the obvious differences that occurred over the course of the 8-week study period.

Figure 1: Relative changes in liver weight, hepatic triglyceride content as well as the liver markers AST, ALT and ALP a marker of kidney health  compared the "control" group (CNEAA | Jegatheesan. 2015)

A period, in which the rodents in the fructose enriched diet group (F) developed NAFLD. A fate the rats in the FCit and the FNEFA group did not share - even though the amount of fructose in their diets was exactly as high as it was in the F group.

Figure 2: Both FNEAA and FCit rodents had a better body composition than the rodents on the NEAA supplemented control diet, but the differences reached statistical sign. only compared to the fructose (F) group (Jegatheesan. 2015)

In that, it is unquestionably worth noting that we are not talking about a mere amelioration of the fructose induced damage. If you look at the data you will notice that the rodents with the alanine, glycine, proline, aspartate, histidine, and serine enhanced fructose enriched diets actually ended up having healthier livers than those on the non-fructose diet... if that's not convincing evidence that the commonly heard, and painfully overgeneralized claim that "fructose is the root cause of all metabolic diseases" is bogus, I don't know.

So, why would you even consider citrulline, if the NEAA combo is better for your liver? 

Well, the reason that the average physique enthusiast, may still choose citrulline as his "fructose buffer" of choice is easy: Firstly, the differences in terms of liver health are not really statistically significant. Secondly and more importantly, though, citrulline triggered a reduction in visceral and total fat mass and a relative increase lean mass that was not observed in the NEAA group. And let's be honest: Isn't this type of body recompositioning effect what many of you are striving for?

What is most astonishing though, is that you could have these fat loss and muscle gain effects not just despite, but maybe even because you're guzzling HFCS drinks all day (obviously we'd have to have a citrulline + baseline diet group to confirm that). If we assume that the results translate 1:1 to human beings, the one thing you had just ~10g of citrulline per day. Is this possible? Well, it is, but let's be honest with ourselves: The inter-group differences between the control and the citrulline + fructose were not statistically significant. So while there were improvements those were not pronounced enough to be of statistical significance even in rodents. It is thus not really surprising that you haven't heard of citrulline as the "get jacked" amino acid very often... even though, evidence that it can help you to get jacked does exist (more).

Bottom line: It is quite astonishing how commonly ignored correlates of high fructose intakes can turn an obesogenic liver killer into a regular energy supplier. I mean, look at the data in the study at hand: Where's the evidence that fructose is worse than any other energy source, when a simple increase in NEAA or citrulline intake does not just nullify its effects but has the rodents on the 60% fructose diet end up leaner and with lower liver fat and better AST and ALT levels than their peers on the control diet (these differences are only partly statistically sign., though).

Citrulline & Glutathione - GSH Amplifies & Prolongs CIT's NO Boosting Effects During + After Biceps Workout | learn more.

So, just as Jegatheesan et al. say: When combined with NEAAs or citrulline, fructose is not just harmless, but can even "produced an overall change in nutritional and metabolic status, with lower body weight and altered body composition, [in spite of identical" food/energy [...] among groups" (Jegatheesan. 2015). Unfortunately, the precise mechanisms involved still need to be investigated. Jegetheesan et al. are yet relatively convinced that NEAAs and citrulline act via different pathways: "NEAAs may act through GCN2, citrulline could act on the liver via PPARa and the down-regulation of SREBP1c, for example, via protein kinase B and mTOR pathway, but also via the improved insulin sensitivity enabled by peripheral Arg bioavailability" (ibid). Just as it is the case for the applicability in humans, though, these hypotheses require future experimental verification | Comment!

References:

• Bortolotti, Murielle, et al. "Effects of dietary protein on lipid metabolism in high fructose fed humans." Clinical Nutrition 31.2 (2012): 238-245.
• Jegatheesan, Prasanthi, et al. "Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease." Clinical Nutrition (2015).
• Jegatheesan, Prasanthi, et al. "Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats." The Journal of Nutrition (2015): jn218982.
• Marchesini, Giulio, et al. "Nonalcoholic fatty liver disease a feature of the metabolic syndrome." Diabetes 50.8 (2001): 1844-1850.
• Osowska, Sylwia, et al. "Citrulline modulates muscle protein metabolism in old malnourished rats." American Journal of Physiology-Endocrinology and Metabolism 291.3 (2006): E582-E586.
• Theytaz, Fanny, et al. "Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans." The American journal of clinical nutrition 96.5 (2012): 1008-1016.
• Volynets, Valentina, et al. "Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD)." Digestive diseases and sciences 57.7 (2012): 1932-1941.

Three Reasons Why Your Doctor May Falsely Believe Your Kidney, Liver or Heart Were Damaged If You Get Blood Work Done Without Adequate Rest After Intense Workouts

Sometimes lab values are deceiving - specifically if allegedly pathological elevations of kidney, liver and (heart) muscle enzmes are a perfectly physiological reaction to exercise. 

You already know reason #1. The heavily increased creatine kinase (CK) levels I've discussed in a previous article at length may look exactly as if you were about to have a kidney failure.

In fact, the CK-levels can be elevated more than 100-fold after an intense workout (Pettersson. 2008). Accordingly, Mougios, et al. (2007) attempted to develop revised reference values for athletes in their 2007 study. The scientists' test revealed that CK levels of >1000 IU/L in male and 513 IU/L in female athletes would be better cut off levels for athletes who are still training than the regular upper limit of <208 IU/L.

If you want to avoid muscle damage, you may try BFR and hypoxia training.

BFR, Cortisol & GH Responses

BFR - Where are we now?

Hypoxia + HIIT = Win?

BFR for Injured Athletes

Strength ⇧ | Size ⇩ w/ BFR

Training & Living in Hypoxia

Closely related to the CK-levels, which are unquestionably the #1 reason your doctor may want to call an ambulance, despite the fact that all you're suffering from is heavy deep onset muscle soreness, are elevated transaminase levels (see time course of elevation in the Petterson study).

Figure 1: Changes in serum enzyme levels after exercise in trained and untrained subjects in response to 15 minutes treadmill running and an 8k run (Fowler. 1962).

In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), are considered to be an indicator of liver damage. In athletes, however, elevated levels of both of these enzymes are - just like elevated creatine kinase levels - a mere sign of exercise induced muscle damage.

As the data from a 1962 study by Fowler, et al. indicates, even 15 minutes on a treadmill can lead to significantly elevated ALT (back in the day the enzyme was still called "GPT") and AST ("GOT") levels. An 8k run can increase ALT and AST by more than 150% (see Figure 1). In that the extent of ALT & AST elevations probably depends on the individuals' susceptibility to exercise induced protein breakdown, which is the actual reason the enzymes which breakdown the protein debris in the liver are elevated.

As it is the case with the creatine kinase enyzmes, many primary physicians and scientists are unaware of the connection and the long-lasting elevations of serum transaminases in response to hard workouts.

Figure 2: In trained marines AST (=SGOT), ALT (=SGPT) react significantly less pronounced (Schlang. 1961)

Against that background it's hardly surprising that Pertusi et al. report in a 2007 paper that the exercise-induced elevations of aminotransferases is also the reason that anabolic steroid induced liver damage has overreported. An overreporting of which the scientists say that is has "in turn, biased physicians against considering muscle damage as a possible cause for aminotransferase elevations (Pertusi. 2001).

Chronically elevated liver enzymes should still not be taken lightly. Even if they don't indicate liver damage, they could be a sign of chronic overtraining. After all, Hunter et al. (1971) were able to show that training reduces the initially exuberant increases of the aminotransferases significantly.

Speaking of not taking lightly, one thing you shouldn't take lightly either is your doctor's suspicion that you may have developed a heart disease. 

More specifically, Elliott and La Gerche have recently been reporting that strenuous endurance exercise (SEE) is associated with acute depression of RV systolic function, thus suggesting that exposure to repeated bouts of SEE can have potential long-term consequences. La Gerche and Claessen argued that left atrial pressure is increased during SEE, thereby increasing pulmonary artery pressure. As Fabian Sanchis-Gomar et al. point out in an editorial comment, they thus stated

"that frequent episodes of increased RV work induced by long-term SEE can promote compensatory RV remodeling, increase myocardial damage biomarkers such as troponins and B-type natriuretic peptide, or even accelerate heart failure (HF)" (Sanchis-Gomar. 2015). 

The Spanish researchers do yet highlight that to the best of their knowledge the bulk of the evidence available supports that the above mentioned alterations which include among other the cardiac-specific creatine kinase marker are rather transient, with a dose-effect relationship existing for exercise intensity and duration.

"Physicians and health professionals should be aware that healthy individuals who engage in SEE sport events could exhibit acute, transient cardiological features that are apparently compatible with cardiac diseases, yet these alterations are attributable in most cases to transient physiological responses rather than pathological status"(Sanchis-Gomar. 2015).

Against that background, it may be a good idea to take two weeks off in order to retest, if your doctor says that your biomarkers suggest that you may be suffering from heart disease.

Read the previous article for all the details on CK elevations.

Bottom line: While you should never take the "bad news" your doctor may have for you lightly. It may be wise to evaluate, whether allegedly pathological changes in creatine kinase (CK), transaminases (ALT & AST) and / or strange alterations in troponins and or B-type natriuretic peptide that suggest you may be suffering from kidney, liver or heart damage may simply be the result of a recent workout.

Since CK, ALT and AST can remain elevated for more than a week (see time course of elevation of AST in Petterson's study), it would be best to take two weeks off of strenuous training before you do a re-test which will then - hopefully - confirm that the disconcerting abnormalities were nothing but a result of your last intense workout | Comment on Facebook!

References:

• Elliott, Adrian D., and Andre La Gerche. "The right ventricle following prolonged endurance exercise: are we overlooking the more important side of the heart? A meta-analysis." British journal of sports medicine (2014): bjsports-2014.
• Fowler, William M., et al. "Changes in serum enzyme levels after exercise in trained and untrained subjects." Journal of applied physiology 17.6 (1962): 943-946.
• Hunter, J. BARRY, and JERRY B. Critz. "Effect of training on plasma enzyme levels in man." Journal of applied physiology 31.1 (1971): 20-23.
• Mougios V. Reference intervals for serum creatine kinase in athletes. Br J Sports Med. 2007 Oct;41(10):674-8. Epub 2007 May 25.
• Pertusi, Raymond., R. D. Dickerman, and W. J. McConathy. "Evaluation of aminotransferase elevations in a bodybuilder using anabolic steroids: hepatitis or rhabdomyolysis?." JOURNAL-AMERICAN OSTEOPATHIC ASSOCIATION 101.7 (2001): 391-394.
• Pettersson, Jonas, et al. "Muscular exercise can cause highly pathological liver function tests in healthy men." British journal of clinical pharmacology 65.2 (2008): 253-259.
• Sanchis-Gomar, Fabian, et al. "Long-term strenuous endurance exercise and the right ventricle: Is it a real matter of concern?." Canadian Journal of Cardiology (2015).
• Schlang, Captain HA, and C. A. Kirkpatrick. "The effect of physical exercise on serum transaminase." The American journal of the medical sciences 242.3 (1961): 338-341.

Rhabdo & Liver Failure or Just an Intense Leg-Workout? What Your Doctor Does not Know About AST, ALT and CK - CK-Values of 10,000 IU+ Will not Necessarily Kill You

Intense training sessions will always increase ALT, AST & CK. Unfortunately doctors will never learn that in med-school.

I don't remember the exact number, but I am afraid that I have promised to write and post this article at least a dozen of times. After getting another three questions pertaining to elevated AST, ALT and CK values on the last lab report within the last two weeks, only, I think it's about time to live up to this promise and translate + update an older, German article, I've written about the very same subject several years ago (note: I decided against translating it, but will write a complete new article - with updated facts, obviously).

Let's first see what we are actually talking about. Typically you went for a routine blood work and get a call from the nurse that there was something wrong with your "liver"- or "muscle-enzymes". You are summoned into the doctor's office, where your concerned doctor is already waiting at his desk looking at you as if you were a criminal and an idiot: "Do you do steroids?"

No, creatine is not the reason your creatine kinase levels are increased?

Creatine Doubles 'Ur GainZ!

Creatine, DHT & Broscience

Creatine Better After Workout

ALA + Creatine = Max Uptake?

Creatine Blunts Fat Loss?

Build 'Ur Own Buffered Creatine

That's the standard questions you will hear, when you enter the office - usually with this accusing undertone that says: "There you have it, now you have to suffer the consequences". Usually, this is the moment, when your mind starts racing: "What does he want, I did never... oh, my! Maybe the wise-asses over at the FDA were right after all? Was one of the supplements I took tainted..."

*STOP!* Agonizing about what you could possibly have done wrong is not going to help you here. This is all the more true if we take into account that tit is very likely that you did not do anything wrong at all. Against that background I'd suggest you stop panicking and start reading today's SuppVersity article, which will inform you about (1) what exactly AST, ALT and CK are, (2) why your doctor is so concerned about their elevation, and (3) how you can find out if he is rightly concerned or you are in the midst of a fitness version of Much Ado About Nothing.

What exactly are AST, ALT and CK & how do you read them (in contrast to your Dr)

On the text-book level this question is easy to answer. I guess it'd be best if we started with the proper name, of which you'll see that they already give away half of the solution to the mystically ALT, AST and CK elevations and the rarely measured but often likewise elevated lactate dehydrogenase and myoglobin levels.

Table 1: Time in h before ALT, AST, etc. (➚) exceed reference, (☆) peak, (➘) are back to normal (Petterson. 2007)

• ALT - alanine transaminase
  formerly SGPT, serum glutamic-pyruvic transaminase
• AST - aspartate transaminase
  formerly SGOT, serum glutamic oxaloacetic transaminase
• CK - creatine kinase
• LD - lactate dehydrogenase
• Myoglobin - iron- and oxygen-binding protein

Instead of tackling them alphabetically, we will start with "C" as in "creatine kinase", because this muscle enzyme, every SuppVersity reader knows as a frequently used, but pretty unreliable indicator of muscle damage is - at least in my experience - the #1 reason you may receive an overanxious call from your doctor's receptionist.

Elevated CK = Intense workout ↛ rhabdomyolysis ⇆ cardiac infarction

Did you ever notice that most lab reports list two types of creatine kinase? No? Usually they are listed as CK-MM and CK-MB and denote two out of a total seven isoforms scientists and doctors who specialize in muscular disorders are regularly testing for:

• 

  Suggested Read: "Why training over the full ROM counts" | more

  CKB ➫ brain | BB-CK
• CKBE ➫ ectopic expression | n.a.
• CKM ➫ all muscle | MM-CK
• CK-MM  ➫ mostly skeletal muscle
• CK-MB ➫ mostly heart muscle
• CKMT1A, CKMT1B ➫ ubiqu. mitochondrial CK
• CKMT2 ➫  sarcomeric mitochondrial CK

For your purposes the funky mitochondrial CK values are irrelevant and testing brain CK levels is usually not necessary either. Knowing your CK-MM and CK-MB, however, can come very handy to exclude identify which muscles are affected (note: Being lovesick does not lead to elevated CK-MB levels ;-)

The CK-MM differntial diagnosis: Have you sustained a cardiac infarction?

I should have mentioned it before, but I believe you are smart enough not to take this article as an invitation to recklessly ignore your Dr's calls. The first thing you would want to do, when the doctor's receptionist is calling it to ask her for the exact CK-MM and CK-MB values.

Tip #1: Always insist on a print-out of all your lab values. The receptionist may say that she cannot pass confidential health information via the telephone, but neither she nor your doctor have the right to keep all or parts of your medical records from you. You paid for the lab report, so it's your property and the least your doctor can do, is handing you a copy or printout of the results. File the sheets in a folder for reference and make sure you never lose that folder.

Their ratio, i.e. the ratio of "skeletal specific" and "heart speficic" creatine kinase, can tell you whether it makes sense / is necessary to further investigate the presence of weak and not even noticeable cardiac infarction.

• A follow up on your heart health is indicated, if CK-MB is elevated and higher than 5% of the total CK (CK-MM) value | example: CK-MB = 200 + CK-MM = 1000

Despite the fact that the 'text-book' ratio of CK-MM to CK-MB for muscle is 99:1, the balance can be slightly off in response to intense exercise, even in the absence of cardiac damage. On the other hand, ca. 25% of the patients with acute myocardial infarctions and symptoms like chest pain, shortness of breath etc. don't even have elevated CK-MB levels, when they present in the ED (Karras. 2001).

Irrespective of all uncertainties, it is very unlikely that your heart has actually taken a beating, if you are and have always been symptom free and have a high CK-MM:CK-MB ratio. This is particularly true if you have been training in the days before the blood draw.

Figure 1: Serum creatine kinase levels (in µkat/L) of perfectly healthy young men after a single intense full-body workout (left); exercise selection (right) - all exercises were performed for 3 sets à 12 reps with 70% of the 1-RM max, the average total weight moved during a single workout was >10 metric tonnes (Petterson. 2007)

As the data in Figure 1 goes to show you, increased levels of creatine kinase in response to strenuous physical activity, such as the standardized resistance training regimen (full body, 3x12 reps on each exercise, training to failure, 60s rest between sets; total training volume in weight units 10,500kg) in a 2007 study by Petterson et al. are perfectly normal. If you look closer, you will also relize that ...

1. the creatine kinase elevations peaked 3-4 days after the workout
2. the peak values vary from 'well within range' (= within the green box) to 6x above normal

In subjects 9, 11, 12 and 15, who had CK values that peaked 158x-278x higher than the official upper reference limit for the tests Petterson et al. used (note: most labs will use IU references, where the 3.2 µkat/L from Petterson's study would equal 206IU/L), the amount of myoglobin, which is likewise an indicator of severe skeletal muscle damage, was even above the upper detection limit (2999µg/L). Without the accompanying information that the previously untrained subjects have been hitting the weights, it is thus more than likely that most doctors who are looking solely at the lab raport would assume the 15 subjects from the study at hand were suffering from borderline to full-blown Rhabdomyolysis (Greek: ῥαβδω rhabdo- striped; μυς myo- muscle; λύσις –lysis).

Tip #2: Tell your doctor, when you've been lifting before the blood draw! If your medical practitioner does not know you and your training practices you can hardly blame him for being concerned about your health, when your creatine kinase levels are 10x-200x elevated.

It goes without saying that neither the 'low -', nor the four 'high responders' in the Petterson study had to be transferred to the emergency room for impeding kidney damage in response to full-blown rhabdomyolysis and that despite the fact that their levels were - due to their low training status - much more pronounced than those of the average athlete.

If you train like an athlete you will have the creatine kinase levels of an athlete

Irrespective of the protective effects of regular exercise, even professional athletes have chronically elevated creatine kinase levels. Yet, despite the fact that a 1984 study by Jaffe et al. was by no means the first to conclude that a substantial fraction of professional athletes have elevated CK-MM and CK-MB levels (Jaffe. 1984), Vassilis Mougios' 2007 paper "Reference intervals for serum creatine kinase in athletes" was the first to present a set of scientifically verified reference intervals for creatine kinase levels in athletes (Mougios. 2007). 

Figure 2: Experimentally verified CK values in male and female athletes and calculated CK reference ranges for athletes and non-athletes (Mougious. 2014))

If you are training like an athlete, the reference values Mougious calculated based on data from 483 male athletes and 245 female athletes (aged 7–44 years; see Figure 2) are thus a much better benchmark to determine whether you should or shouldn't be concerned about the red exclamation mark on your lab report.

What you (could) have learned today: Before we are about to take a closer look at the "liver values" ALT and AST, next week, let's briefly summarize what you you could have learned today that may help you, when you're summoned to the doctors office and your doctor wants to call the ambulance to save your kidneys from the consequences of your "rhabdo":

• Elevations of >10,000IU can occur and last for days after intense workouts.
• Regular training lowers the exercise induced CK leakage from the 10,000+ range back to the 500-1,500IU range.
• Nevertheless, the CK levels of athletes will always be higher than that of sedentary controls.
• It can take up to a week for your CK levels to return to baseline. If you want to make sure that your high CK levels are caused by exercise and nothing else, you will have to take a full week (best 14-days) off, before you retest.
• If the levels don't return to "normal" when you rest and / or if you train at a frequency and intensity that leads to chronically elevated CK levels, don't ignore this problem. Try to get to the bottom of it and make sure it's not a health issue - as soon as that's done, adapt your training regimen and rewrite it from "insane" to "intense, but sensible".

Before you go, I would like to point out that your doctor is right to be concerned. Even if he knew about the effects of exercise (most doctors don't), 99% of his patients are not going to the gym and doing breathing squats for reps. For those people CK-values in the 1k+ range are a serious cause of concern. Learn more about elevated AST and ALT levels in the follow up!

Reference:

• Jaffe AS, Garfinkel BT, Ritter CS, Sobel BE. Plasma MB creatine kinase after vigorous exercise in professional athletes. Am J Cardiol. 1984 Mar 1;53(6):856-8.
• Karras DJ, Kane DL. Serum markers in the emergency department diagnosis of acute myocardial infarction. Emerg Med Clin North Am. 2001 May;19(2):321-37. Review.
• Mougios V. Reference intervals for serum creatine kinase in athletes. Br J Sports Med. 2007 Oct;41(10):674-8. Epub 2007 May 25.

Study Says: Prohormone "1-Andro" Works, But It's Bad for You! Plus: What About Other Prohormones or Steroids Such As Androstenedione, DHEA, Testosterone & DECA?

If you ask your doctor about prohormones, he will tell you that they don't work and make you sick... don't argue with him, 'cause that's his job and believing in this half-truth is certainly good for your health.

Published ahead of print in the Journal of Applied Physiology is a paper on the ergogenic and healht effects of 3b-hydroxy-5a-androst-1-en-17-one aka 1-ANDRO. According to Jorge Granadosm, Trevor L. Gillum, Kevin M. Christmas, and Matthew R. Kuennen, the authors of the said paper, this is the first official evaluation of the viability of prohormone supplements ever since the Anabolic Steroid Control Act was amended in 2004 (Granadosm. 2013b) - a statement of which you as a SuppVersity reader know that it is true only if we are talking about the experiments, noto about the papers, though. The one at hand, is after all paper #2 Granados et al. are publishing.

"I knew I know this study!"

Yes, you heard me right. The researchers from the West Texas A&M University, the California Baptist University and the University of Texas at Austin have actually published a paper with the main results of this experiment  in the International Journal of Exercise Science earlier in 2013 (Granados. 2013a) and I guess some of you may even remember that they've read about it here at the SuppVersity.

Figure 1: Relative changes in muscle mass (total change above the bars) and kidney, "liver" and lipoprotein metabolism after four weeks on a 1-AD clone; note SGOT is the old name for AST (Granados. 2013a)

I mean, don't you recognize Figure 1? No? That's fine, because it means, you did not realize that I simply copied it from a short-new item I published on March 09, 2013 (go back). This has obviously little to do with plagiarism, or laziness ;-) I simply thought it may be worth taking a loser look at the study. A look that goes beyond the short-news item from March and, as the headline already announced, even beyond the effects of "1-Andro".

Evidence from previous trials using other (pro-)hormone: The study at hand is not just the first since the amendment of the Anabolic Steroid Control Act it is also one of the few studies that which evaluate the effects of (pro)hormones on the outcomes of resistance training regimen in young men, anyway. Aside from the information on 1-AD my cursory search of the databases revealed the following information about "alternative" agents:

androsterone (100mg/day for 4 weeks), normal young man: no increase in strength or size gains, no difference in effects on body com, no increase in testosterone, increase in estradiol and estrone, reduced HDL levels that remained low for one months after the supplementation (King. 1999)

DHEA (150mg/day for 8 weeks), normal young men: While it does work in older men & women (Villarea. 2006), it has no effect on total testosterone, estrone, estradiol, estriol, lipids, and liver transaminases, identical strength and size gains as in placebo (Brown. 1999)

nandrolone (600mg weekly for 12 weeks), young men with HIV: significant increase in total body weight, 5.2kg lean mass in 12 weeks, significant increases in muscle size, 14.4–53.0% strength gains, no changes in fasting serum total cholesterol and triglycerides (LDL and HDL not measured; cf. Sattler. 1999)

testosterone (600 mg of testosterone enanthate (TE) or placebo weekly for 10 weeks), normal young men: Increases in fat-free mass (6.1±0.6 kg) and muscle size (triceps area, 501±104 mm²; quadriceps area, 1174±91 mm²), increases in muscle strength (bench-press strength, 22±2 kg; squatting-exercise capacity, 38±4 kg), neither mood nor behavior was altered in any group, increase in serum creatinine concentration (1.0 mg/dl to 1.1mg/dl),  no change in plasma concentrations of total and LDL cholesterol and triglycerides, HDL  cholesterol  decreased  significantly, but less in the TE + resistance training (-10%) vs. resistance training only groups (-12%; cf. Bhasin. 1996)

What strikes me as odd is the fact that the HDL decrease with in the Basin study occurred only when the participants worked out. In the sedentary participants who received the same dosage of testosterone enanthate, such effects were not observed.

Here is the elevator pitch on the study design

The scientists recruited 17 resistance-trained males (23±1yrs; 13.1±1.5% body fat) and randomly assigned them to ingest either 330mg/day 3b-hydroxy-5a-androst-1-en-17-one (PH; n=9) that were "enhanced" with 50mg of 6,7,-dihydrobergamottin, a grapefruit flavenol member of the furanocoumarin family that inhibits cytochrome P450-34A (Edwards. 1996), or 330mg/day plain maltodextrin (PLA; n=8). During the following 4 weeks, the subjects participated in a 16 session of structured resistance-training.

The training plans were hypertrophy specific and personalized. It is thus not really surprising that all subjects gained a significant amount of lean mass. What is surprising, though is how pronounced the inter-group differences were.

While the "1-Andro cycle" lead to significant increases in lean body mass 6.3±1.2%, decreased the total body fat mass by 24.6±7.1%, and increased the back squat 1-RM and average strength by 14.3±1.5% and 12.8±1.1%, respectively, the participants who were "on sugar" experienced only minor changes in body composition: 0.5±0.8% increases in lean mass and a 9.5±3.6% reduction in body fat. Needless to say that these changes, as well as the increased back squat 1-RM and average strength of 5.7±1.7% and 5.9±1.7% were also statistically different from the pronounced gains in the "1-Andro" group. In fact, they look pretty much like the almost frustatringly slow, but persistent gains you'd expect to see in already highly trained subjects within only 4 weeks (Note: The subjects in the placebo groups, i.e. the "low gainers", had 2 years less training (4.5y) experience than the high gainers in the "1-Andro group" with their 6.3y of resistance training history).

But that cannot be good for your health, can it?

If you want to be accepted as a scientists, and still do research into anabolic steroids or prohormones, you obviously must not refrain from pointing out that the previously described beneficial effects on body comp came at the expense of a 38.7±4.0% reduction in HDL (p<0.01), a 32.8±15.05% elevation in LDL (p<0.01), and elevations of 120.0±22.6% and 77.4±12.0% in LDL/HDL and C/HDL; respectively (both p<0.01), due to which the prohormone group got from a groovy 2.2:1 ratio for total cholesterol / HDL (everything < 3.5 : 1  is "optimal") up right to the edge of the 5:1 + danger zone (4.8 ± 0.6). In addition to that, the researchers observed

• increases in serum creatinine (19.6±4.3%; p<0.01), a breakdown product of creatine phosphate in muscle,
• elevated aspartate transaminase (AST or SGOT) levels (113.8±61.1%; p=0.05), which could be an indicator of liver strain (they are elevated by any form of strenous training, but the elevations in the control group were not significant),
• significant reductions in serum albumin (5.1±1.9%; p=0.04), which could be a consequence of the strain on the liver or the kidneys, but are still much less pronounced than in patients with "real" liver disease or nephrotic syndrome,
• increases in alkaline phosphatase (ALP; 16.4±4.7%; p=0.04), which could indicate a beginning obstruction of the bile ducts, and
• elevated glomerular filtration rats (18.0±3.3%;p=0.04), which tell you that the kindeys are working overtime.

All the above are changes you will see in response to heavy resistance training, anyway, but in view of the fact that they are much less pronounced / non-existent in the control group, the scientists are probably right when the conclude that the improvements in body composition you can achieve with 300mg of 1-Andro per day come at the expense of "[c]ardiovascular health and liver function".

You want to know what the size of that expense is?

Well, I already said that the changes in ALT & Co are difficult to judge, I've seen much higher AST & ALT levels than those 41.4 IU/L and 49.4 IU/L (reference ranges are < 41 IU/L and <48 IU/L) after only one training sessions. In the recreationally trained men in Pettersson's study from 2008, for example (see figure 2) - against that background, I would not worry about the alleged liver enzymes first... they are after all also muscle enzymes and last time I checked, converting one amino acid into another - which is what "trans-aminases" do - was not per se a bad thing, per se ;-)

Figure 2: Changes in AST in response to a single 1h weight lifting sessions . an "NO!", the recreationally trained subjects didn't die from liver failure. Surprise? Not really!  (Pettersson. 2008)

The decline in HDL to a pathetic 27.3 mg/dl, on the other hand, is definitely something you should worry about.

If you read the latest SuppVersity Facebook News about the role HDL plays not just in metabolic and heart health, but also in brain health (read more), you have at least three good reasons? And if you want a number on one of them, I can give you the estimated difference for the risk of a major cardiovascular event that corresponds to the -18.7 mg/dl decrease in HDL, the subjects in the 1-Andro study experienced. It's roughly 18% - at least if you put some faith into one of the most recent of the few prospective case–cohort studies with healthy subjects (Kappelle. 2011).

So I guess, if you want to worry about, this 18% increased risk, you better worry about the effects on your blood lipids, than about elevated transaminases, of which I am not even sure that you wouldn't have to blame them on side-effects / interactions of the added dihydrobergamottin in the prohormone formula.

So it's not worth it? Whether you personally would agree that "[g]iven these findings [...]the harm associated with this particular PS [prohormone supplement] outweighs any potential benefit" (Grandos. 2013b) is obviously a question of perspective; and I am not the one to tell you which perspective is right for you. Everyone picks his own poison! And having read this article, you are at least better informed than you'd be after studying the colorful advertisement banners on the Internet.

References:

• Bhasin, S., Storer, T. W., Berman, N., Callegari, C., Clevenger, B., Phillips, J., ... & Casaburi, R. (1996). The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. New England Journal of Medicine, 335(1), 1-7. 
• Brown, G. A., Vukovich, M. D., Sharp, R. L., Reifenrath, T. A., Parsons, K. A., & King, D. S. (1999). Effect of oral DHEA on serum testosterone and adaptations to resistance training in young men. Journal of Applied Physiology, 87(6), 2274-2283. 
• Edwards, D. J., Bellevue, F. H., & Woster, P. M. (1996). Identification of 6', 7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug metabolism and disposition, 24(12), 1287-1290.
• Granados J, Gillum T, Hodges C, Kuennen M. (2013a) 3-hydroxy-5alpha-androst-1-en-17-one Enhances Muscular Gains but Impairs the Cardio-metabolic Health of Resistance Trained Males. International Journal of Exercise Science. TACM.
• Granados J, Gillum T, Hodges C, Kuennen M. (2013b) Prohormone supplement 3b-hydroxy-5a-androst-1-en-17-one enhances resistance training gains but impairs user health. Published online before print December 31, 2013. 
• Kappelle, P. J. W. H., Gansevoort, R. T., Hillege, J. L., Wolffenbuttel, B. H. R., & Dullaart, R. P. F. (2011). Apolipoprotein B/A‐I and total cholesterol/high‐density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C‐reactive protein. Journal of internal medicine, 269(2), 232-242.
• King, D. S., Sharp, R. L., Vukovich, M. D., Brown, G. A., Reifenrath, T. A., Uhl, N. L., & Parsons, K. A. (1999). Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men. JAMA: the journal of the American Medical Association, 281(21), 2020-2028. 
• Pettersson, J., Hindorf, U., Persson, P., Bengtsson, T., Malmqvist, U., Werkström, V., & Ekelund, M. (2008). Muscular exercise can cause highly pathological liver function tests in healthy men. British journal of clinical pharmacology, 65(2), 253-259.
• Sattler, F. R., Jaque, S. V., Schroeder, E. T., Olson, C., Dube, M. P., Martinez, C., ... & Azen, S. (1999). Effects of pharmacological doses of nandrolone decanoate and progressive resistance training in immunodeficient patients infected with human immunodeficiency virus. Journal of Clinical Endocrinology & Metabolism, 84(4), 1268-1276.
• Villareal, D. T., & Holloszy, J. O. (2006). DHEA enhances effects of weight training on muscle mass and strength in elderly women and men. American Journal of Physiology-Endocrinology And Metabolism, 291(5), E1003-E1008.

D-Finitively Relevant News: Vitamin D Supplementation Speeds Up Strength Recovery and Lowers Markers of Muscle Damage in Vitamin D-Sufficient Young Subjects

If we were all training at "Muscle Beach", we would probably not need any vitamin D3 caps to get our 25(OH)D levels into the recovery friendly 50ng/ml zone. They would already be there!

Ok, I know this looks odd, but it's really total coincidence that all the interesting vitamin D research is published in the last weeks of the year. Unlike the latest vitamin D articles, i.e.

• "Vitamin D Builds Muscle: 70% Reduction in Myostatin, 45% Increase in Myotube Size in 10 Days" |  learn more
• "Leucine, Insulin & Vitamin D*: A Hypertrophy Boosting Triplet That Does Not Make It From the Dish to the Gym?" | read more

today's SuppVersity article does yet leave little room for speculations about it's real-world significance. I mean, how could it, if the paper it discusses is titled "Supplemental vitamin D enhances the recovery in peak isometric force shortly after intense exercise" (Barker. 2013).

You can learn more about vitamin D at the SuppVersity

Vitamin D Builds Muscle

Leucine, Insulin & Vitamin D

Vitamin D = Fat Synthesizer

Overlooked D-Sources

Vitamin D For Athletes!

Vitamin D Helps Store Fat

The title does yet not "say it all". Moreover, what it doesn't tell you is the most important piece of information. The study period was short (35 days) the dose of vitamin D was relatively high (4,000IU) was conducted with "reportedly healthy and modestly active (30 minute of continuous physical activity at least 3 time/week) adult men with low, albeit normal vitamin D levels (25(OH)D ~ 30ng/ml)! The otherwise almost obligatory question about the potential relevance in "normal" human beings does thus become superfluous - and this is true for all the observations the scientists made, i.e.

• ... the linear relationship between baseline 25(OH)D levels and the increase in serum vitamin D in response to the with an up to 150% increase in subjects in the deficiency zone and less than 50% increases in subjects in the >40ng/ml range, ...
• ... the steady serum calcium levels, which make concerns about potentially kidney damaging increases in calcium from vitamin D3 supplementation obsolete, ...

... and, not to forget, the enhanced recovery in peak isometric force the researchers observed in their subjects after these had performed 10 sets of 10 repetitive eccentric-concentric jumps with a load of 75% of their respective body mass on their shoulders and a 20 sec rest period between each set.

For the researchers this is a model of a "muscle damaging event" (P< 0.05; ≈8% at 24-h), which was, as it was to be expected, associated with an increase in the circulating levels of the "liver enzymes"  alanine (ALT) and aspartate (AST) aminotransferase, of which many medical textbook will tell incorrectly tell you that they would indicate a strain on the liver / liver damage, when they are actually only markers of increase amino acid catabolism. The attenuation (P< 0.05) of the immediate and delayed (48-h, 72-h, or 168-h) increase in these enzymes in the vitamin D supplemented group  is thus an indicator of "muscle protective" or at least general protein sparing effects of supplementally increased vitamin D levels.

Figure 1: Strength recovery (%) from immediately post to 24 post workout, left; serum ALT values immediately after, 24h, 72h, and 168h after the exercise test (Barker. 2013).

The fact that the alleged decrease in muscle damage did not correlate with a decrease in muscle soreness does or doesn't negate the purported muscle protective effects of vitamin D. There is, as you should remember from Alex' excellent articles about DOMS, after all no direct link between ALT, AST, muscle damage and delayed onset muscle soreness, aka DOMS (learn more about DOMS). What is clear, though is that there was no consistent trend in the subjective measures of muscle soreness in the study at hand, so that Barker et al. are right, when they state that "[s]upplemental vitamin D was ineffective at abrogating muscle soreness in the SSC leg" (Barker. 2013). If it's an improvement in pain you are looking for, you'd be better off with one of the techniques Alex' discussed in part I of his article series.

Figure 2: It looks boring, but the linear association between the subjects baseline levels and the change in 25(OH)D and the ceiling effect at ~50ng/ml are also important results of the study at hand (Barker. 2013).

Bottom line: I guess you can't have it all, so I would not mourn over the lack of effect on muscle soreness. I mean, come on (!), this is one out of thousand (literally!) vitamin D studies with real-world relevance for you and me. A study that confirms that getting your 25(OH)D levels into the 50ng/ml range can actually have small, but stat. significant beneficial effects on your exercise performance (without negative effects on calcium, btw).

Furthermore, the fact that this increase to the 50ng/ml+ was achieved in all subjects with "only" 4,000IU D3 within only 35 days and was directly associated to their respective baseline level is an intruiging result on its own (see Figure 2). It does after all provide you with a rough guideline of what you have to do if your next 25(OH)D blood test comes back way below the 50ng/ml margin.

Against that background, there is no reason to frown about the fact that we still don't really know what vitamin D actually does to elicit its ameliorative effects on the performance decline in response to potentially muscle damaging stretch-shortening contraction. This was beyond the scope of the study at hand and cannot be investigated in isolated muscle cells... much contrary to the previously reported anabolic effects in the Petri dish, by the way, which may be exciting, but more or less irrelevant, if we can't observe corresponding increases in muscle hypertrophy in the real world.

References:

• Barker, T., Schneider, E. D., Dixon, B. M., Henriksen, V. T., & Weaver, L. K. (2013). Supplemental vitamin D enhances the recovery in peak isometric force shortly after intense exercise. Nutrition & Metabolism, 10(1), 69.

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'.

---

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.

Lose(!) 33% Body Fat in 10 Days!? The Heavy Metal Obesity Link: Study Shows "Preventive Role" for Inorganic Cobalt in Obesity-Related Diseases.

Image 1: Cobalt - certainly not what you would expect to see at a health food store or pharmacy; with Kawakami et al.'s study this may change in the future (img Alchemist-hp)

"We are living in a toxic world!" - you have probably heard or read this sentence more than once and while I cannot deny that the environmental load of, among others, heavy metals appears to be increasing, I can however tell you that, according to a recent study from scientists from the Tukushima Bunri University in Japan, exposure to some of those heavy metals produces quite unexpected results in a rodent model of the metabolic syndrome and in lean controls. Instead of making them gain weight even more rapidly, the "toxic" (maybe we will have to reconsider that, just as we did in the case of chromium) heavy metal cobalt did not only reduce the weight of the white adipose tissue of the rodents, it increased leptin, adiponectin, and HDL-cholesterol, as well, and thusly "may have a preventive role in obesity-related diseases" (Kawakami. 2011)

This is certainly the 1001st time I am writing this, but I cannot emphasize often enough that the "high fat diet" researchers use in their studies has (in most cases) nothing to do with the Atkins or even a low-carb diet. Its main characteristic is that it is hypercaloric and high in fat and carbs. Please keep that in mind whenever you read about another study on the detrimental health effects of "high fat diets".

For 24days Kawakami et al. fed a group of seven-weeks-old male mice either a standard diet with 357.6kcal/100g or a hypercaloric (cf. red box above) high fat diet (HFD), where the latter induced obesity and dislepidemia within 2 weeks. After this initial phase, i.e. when the HFD mice were already obese and metabolically deranged, the scientists injected the animals with Sodium Arsenite (NaAsO2: 1.0 mg/kg bw), Mercuric Chloride (HgCl2: 1.0 mg/kg bw), Manganese Chloride (MnCl2: 5.0 mg/kg bw), Cobalt Chloride (CoCl2: 0, 1.3, 5.0, 7.5 mg/kg bw) or saline (control).

Figure 1: Modulatory effects of 10 days of heavy metal injection in mice on a high fat diet; values expressed as changes relative to animals on a normal diet (data calculated based on Kawakami. 2011)

Now, if you look at the data in figure 1, you will notice that the administration of Mercuric Chloride may have been most "effective" in ameliorating the HFD-induced increase in white adipose tissue (WAT) mass (HFD +70%; HgCl2 -14% vs. normal fed control), but those "fat burning" effects went hand in hand with profound elevations of the liver enzymes AST, ALT (in this case we can safely assume that these were not coming from the muscle tissue of the animals) and the blood urea nitrogen (BUN) levels, which indicate deteriorations of the kidney metabolism. Manganese and cobalt, on the other hand, had negligible or even beneficial effects (compared to HFD alone) on liver and kidney health and ameliorated the weight gain to +10% and +17%, respectively.

Figure 2: Adiponectin and leptin serum levels and mRNA expression in mice after 10 days on a high fat diet with simulatenous injection of mercury or cobalt; data expressed relative to normal fed control (calculated based on Kawakami. 2011)

What is particularly interesting about cobalt, though, is that it did not simply starve out the adipose tissue by poisoning it (like that was probably the case for mercury), but triggered exactly those metabolic adaptations scientists have been trying to provoke with drugs for years now: elevations in adiponectin and leptin (cf. figure 2), the two adipokines, researchers currently believe to be essential for successful weight loss / maintenance.

Figure 3: pAMPK/AMPK ratio after injection of different dosages of Cobalt chloride (calculated based on Kawakami. 2011)

In a follow up experiment, the scientists, also found that cobalt dose-dependently increases AMPK phosphorylation (for more on AMPK, I would like to refer you to the Intermittent Thoughts series) in white adipose tissue (WAT), muscle and liver of the animals (cf. figure 3). Of the three tested dosages, administration of 5mg/kg CoCl2 per day resulted in the most beneficial AMPK response, while with the maximal dose of 7.5mg/kg the negative / toxic effects appear to prevail (another of these bell-shaped dose-response curves, I guess).

Figure 4: Glucose tolerance test in mice on high fat diet with or without cobalt injections compared to mice on standard diet (control); values in mg/dl (data adapted from Kawakami. 2011)

Now, you are probably asking yourselves: "So what's the catch?". A brief look at figure 4 tells you that is ain't glucose intolerance, as the cobalt treated animals had the exact same response to the glucose tolerance test, as the mice on the normal diet - in other words: cobalt completely reversed the HFD induced glucose intolerance, and it did so not only without negative effects on blood lipids, but in the presence of a profound elevation of HDL levels and a reduction in LDL levels (cf. figure 5).

Figure 5: Relative (to normal fed control) changes in blood lipid in mice on a high fat diet with or without heavy metal injections (calculated based on Kawakami. 2011)

And as if that was not enough, the cobalt injections also eradicated the iincreases in free fatty acids and ameliorated the increase in triglycerides.

From the lab to the bedside?

Last but not least, and I hardly dare showing you this graph, because I would expect that some of you will already be googling a source of injectable cobalt (which would be plain out stupid, before any reliable safety data and confirmation of these results in controlled human trials are available), cobalt had almost identical effects when it was injected to the mice on the normal diet.

Figure 6: Relative changes in body composition and liver and kidney parameters due to heavy metal injection in non-obese mice on a standard diet (calculated based on Kawakami. 2011)

As figure 6 goes to show the mice lost 33% of their white adipose tissue and liver, as well as kidney function did not take a beating (HDL stayed the same, LDL decreased by -1%). Whether we will see a obesity or even just a weight-loss drug based on cobalt in the near future, does yet still seem questionable. In view of the fact that the number of "bad things" (cobalt is in fact an essential nutrient as it is the active center of vitamin B12 = cobal-amin) that have unexpectedly positive health effects is increasing day by day, we do yet obviously have to ask ourselves, whether there may be some major flaws in our current understanding of how our body works and how it deals and is effected by "toxins", oxidants and co.