Wednesday, April 3, 2013

True or False!? Glucosamine Doesn't Help Cartilage Repair. Carcacrol Based Weight Loss Products Shed Body fat. N-Acetyl-L-Glutamine Is Not Worth the Extra Bucks.

Compared being obese and chronically inflamed heavy squats entail a comparably low risk of "wearing off your" joints.  (Spector. 1996)
If I just go by the mere visitor counts the new "True or False" category appears to turn out to be one of the best innovations of the past weeks. That being said, I am happy that many of you have been submitting questions, but had to realize that even those of which I initially thought they would be easy to answer, require more research than I had expected.

Therefore this installment contains one long and two short TOF items, which I came across more or less accidentally in the course of the past week. I hope you enjoy those as well and don't freak out that your inquiry has not been answered this week (tip: you can increase your chance of having your question answered if you pick something simple, like the two latter items in this installment).

 Glucosamine supplements cannot help with cartilage repair

It depends -- Like many of the true or false item the purported benefits of glucosamine supplements on cartilage health belong to those "gems" of common wisdom which have been reiterated so often that everybody is inclined to believe they must be true. Fortunately, science does not operate by the principle of majority rule, which is why you will have to spend reading the following lines if you want to know whether the use of respective supplements is going to help heal your joints.
    More often than not your pain is not (yet) the result of worn of ligaments, but simply a consequence of muscular imbalances. Your shoulder hurts, whenever you bench? Try the impingement no more protocol and reduce or even resolves shoulder pain in 6 weeks (learn more)
  • age related decline in joint health  - there is currently no convincing evidence that "glucosamine modulates ageing phenotype" (Henrotin. 2013), on the other hand the mere absense of long-term studies does not exclude that it may sill have practical value. Benefits are yet only likely to occur if the ability of human chrondocytes to produce glucosamine from glucose declines with age.
  • general prophylaxis - Aside from the by no means unambiguous evidence from animal studies a prophylactic effect of GlcN supplementation in human trials has - as of now - not been presented (Hernrotin. 2014). In this context, a specific weakness of many human studies is the use of inappropriate, often subjective measures instead of reliable MRI or other imaging methods. 
  • treatment of arthritis (OA) - While the general evidence is scarce, it appears as if GlcN could have an ameliorative effect on the progression of OA. Promising evidence that it could help, yet via a pathway much different from the original concept of "providing raw material for joint health" - comes from animal models in which the administration of high doses of glucosamine had ameliorative effects on systemic inflammation (C-reactive protein, TNF-alpha, Largo. 2009). Unfortunately, this is yet another of the many "promises" that has up to now not been reproduced in controlled human studies, in which the administration of allegedly lower amounts of GlcN (1,500 mg) did not affect any of the common markers of inflammation (Nakamura. 2007).
I guess the previously mentioned points are all "nice to hear", but not exactly what you wanted to read about, right? So what about this one, then, ...
  • CCE the paleo glucosamine? You know that despite my frequent allusions to the (a-)buse of "paleolithic" line argumentations, I am alway open for scientific evidence that would prove any of the bazillion "paleo solutions" people are throwing around on the web (no offense to Robb Wolf, here). Therefore I don't want to miss the chance to let you know that at chicken comb extract (CCE)-containing supplement taken in dosages of 4.8g/day yielded significant improvements in pain scores for the dominant and most affected foot of 23 soccer players (Yoshimura. 2012). Aside from the "eat the whole animal" mantra, this is also interesting as far as the production of future supplements is concerned. After all CCE contains hyaluronic acid (glycosaminoglycan) and are thus themselves made up of glucosamine (or rather D-glucuronic acid and D-N-acetylglucosamine). Whether this makes them more or less effective will yet still have to be elucidated.
    prevention / strengthening of cartilage in athletes: The maintenance of joint health in conditions, where the joints are exposed to excessive loads is probably the area of application GlcN is most heavily marketed for. On the other hand, it is also the area that is the least researched. The current scientific consensus is to acknowledge the evidence from two heavily cited randomized, double-blind,
    placebo-controlled trial, of which ...
    • ... one dealt with 121 male patients who had a recent history of acute knee sport injury (Ostojic. 2007) -- the participants received either 1.5 g GlcN (n=62) per day orplacebo (cellulose; n = 59) for 28 days; despite the fact that the GlcN group demonstrated significant improvements in knee flexion and extension, neither the pain nor swelling subsided
    • ... the other analyzed the effect of three months 1.5g or 3.0g of GlcN on the 21 male college aged soccer players (19–22 years of age, mean 20.3) and compared the outcomes to 10 male age-matched college students (Yoshimura. 2009) -- the administration of the supplement decreased the urine levels of CTX-II, but the observed reduction of this marker of collagen turn-over was transient and disappeared after withdrawal of the administration.
    In view of the fact that the significance of the reduced CTX-II levels in the Yoshimura study is not clear these are promising, but by no means conclusive results which would suggest that strength trainees could benefit from the chronic and timely initiated supplementation of 1.5-3.0g of GlcN per day.
Another thing to keep in mind is that therapeutic doses start at 1,500mg per day (information on optimal dosing regimen for different purposes, age groups, etc. are lacking - also because the bioavailability of glucosamine is highly species dependent and the available literature on horses has little to no value for human beings; cf. Hernrotin. 2013).

There is still the unresolved issue of adequate vs. excessive dosages

While the recommended dosage may be enough to achieve serum concentrations of 10µm which are 1-2x more than those the average human being will have floating around in the non-supplemented state, these are still 50x-500x lower than the concentrations scientists use in the petri-dishes of the in-vitro studies producers of respective supplements like to cite to provide evidence for the efficacy of their products (Largo. 2003; Block. 2010).

Does glucosamine precipitate or even cause insulin resistance? While it probably ain't much of a problem with short term administration of low doses of glucosamine (1g in 2x500mg dosages is safe; cf. Muniyappa. 2005), taking glucosamine in amounts as it would be necessary to achieve serum levels similar to those that have been shown to actually work in in-vitro studies, will almost certainly induce muscular insulin resistance (Largo. 2003; Bailey. 2004; Block. 2010). Moreover, pre-existing insulin resistance (Pham. 2007), as well as diabetogenic diets (Chien. 2009) and/or systemic inflammation (Biggee. 2007) appear to increase the risk of experiencing this nasty side-effect as a consequence of the chronic ingestion (6+ weeks) of dosages of 1.5g+ per day (Dostrovsky. 2011). And let's be honest the sentence "Owing to limitations in study design, conclusions based on studies that report adverse affects of GlcN on insulin sensitivity and glucose tolerance in pre-diabetic subjects are suspect" by the means of which a 2011 review written by employees and counselors of Cargill, a major producer of respective supplements, tries to refute the aforementioned negative scientific evidence is at least as "suspect" as the studies the review is criticizing (Simon. 2011) - no?
With all that being said, the usefulness of glucosamine supplements as a means to prevent, let alone treat cartilage degeneration is unquestionably overblown. This goes irrespective of the existing in-vitro evidence of the stimulatory effect very high concentrations of GlcN exert on their own usage and incorporation and my - at least in part - be due to another, hitherto overlooked, bottleneck that limits our bodies capacity to use the the "raw material" in the way we intend it.

Now that you have the evidence right in front of you I'll leave it up to you to decide whether you want to take the (by no means non-existent) chance that the chronic ingestion of high dosages (at least 3g/day) of GlcN could ward of some of the wear and tear of your workouts or whether you simply stop squatting your 1-RM max for reps using a horrible technique and thus ruining not just your knees, but also your back.

You should be aware, though, that the latter does imply that you trust the Cargill guys' judgment that the hitherto published animal and human studies have "limitations" and any "conclusions based on studies that report adverse affects of GlcN on insulin sensitivity and glucose tolerance in pre-diabetic subjects are suspect" (Simon. 2011; for more info see red box to the right).

Carvacrol supplements will promote weight loss

False -- Despite the fact that a recent study in mice shows that the administration of isopropyl-ortho-cresol aka cravacrol, the predominant monoterpene phenol from the essential oils of plants from the Labiatae family (Origanum, Satureja, Thymbra, Thymus, and Coridothymus), is a potent inducer of hepatic AMPK and sirtuin-1 activity (Kim. 2013), the currently available supplements are so hilariously underdosed that even the researchers could not deny themselves the following side kick:
Cravacrol could work, if there was a supplement with adequate amounts of it on the market (data based on Kim. 2013).
"The daily carvacrol intake of the mice in our study (100 mg/kg body weight) was equivalent to an intake of approximately 8.1 mg/kg human body weight (486 mg/60 kg person), when calculated on the basis of normalization to body surface area as recommended by Reagan-Shaw et al. and the US Food and Drug Administration.

The daily doses of commercial dietary supplements range from 9 to 288 mg carvacrol (0.15–4.8 mg/kg body weight) for a 60 kg human." (Kim. 2013)
This spares me to tell you that you are wasting your money, if you throw one of the carcacrol based fat burners into your virtual or real shopping basket.
On a more general note: Irrespective of any dosage issues, it is by no means sure that any of the many "proven" anti-inflammatory weight loss agents, i.e. herbs & co that help reduce weight gain in rodents on HFD and/or help obese and metabolically deranged individuals to lose weight will do anything at all in healthy, insulin sensitive, non-inflamed, normal-weight individuals (e.g. "Epigallocatechin Gallate (EGCG), Capsaicins, Piperine & Carnitine: Rather a Health Than a Fat Loss Stack?", read more). In other words: "Not everything that's good for your obese neighbor will be beneficial for you, as well."

Due to its stability in water N-Acetyl glutamine is way superior to regular l-glutamine

False -- Irrespective of the never-ending debate on the usefulness of glutamine supplementation for hard-working athletes (learn more), respective supplements are still part of the most commonly used bulk-powders among bodybuilders, physique athletes and average gymrats. Contrary to the potential benefits of respective supplements, which can, despite being far from scientifically established, not be denied altogether, there is one thing that's about as sure as the eggs I had for breakfast: The allegedly more stable N-acetyl variety of glutamine (NAG) does not just taste like **** it is also a complete waste of money and probably less effective than the cheap free-form glutamine you can buy for a couple of pennies at every of the major bulk suppliers on the Internet.
Figure 1: Glutamine content in the blood of 15 pigs (15–20 kg weight) maintained on either a 1kg/day standard diet (C) or C + 8 g L-glutamine and C + 10.5 g N-acetyl-L-glutamine provided at 1000 g/day after "breakfast" (333g of the chow) and detailed analysis of intact glutamine and glutamic acid in the jejunum mucosa, after 180min of intestinal infusion (Arnaud. 2004)
After you have taken a look at the data in figure 1, any further elaborations that go beyond the confirmatin f the high accuracy and usefulness of porcine models for human digestion and metabolism (cf. Litten-Brown. 2010) should be dispensable... as dispensable as NAG supplements, by the way ;-)

That's it for today: As mentioned in the introduction, I am well aware that some of you will be missing their suggestions, but I have to say that answering those inquiries in more than just a "probably no", "probably yes" fashion takes its time. No reason for the rest to keep submitting suggestions, I will keep track of them and have already done some research into the more complex stuff, which may give rise to a post of their own in the future.

  • Bailey CJ, Turner SL. Glucosamine-induced insulin resistance in L6 muscle cells. Diabetes Obes Metab. 2004 Jul;6(4):293-8. 
  • Biggee BA, Blinn CM, Nuite M, Silbert JE, McAlindon TE: Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis. Ann Rheum Dis 2007, 66:260-262. 
  • Block JA, Oegema TR, Sandy JD, Plaas A:  The effects of oral glucosamine on joint health: is a change in research approach needed? Osteoarthr Cartil. 2010; 18:5–11. 
  • Chen HC, Shah S, Stabler TV, Li YJ, Kraus VB: Biomarkers associated with clinical phenotypes of hand osteoarthritis in a large multigenerational family: the CARRIAGE family study. Osteoarthr Cartil. 2008; 16:1054–1059. 
  • Chien CS, Cheng SC, Wu HT, Tsao CW, Cheng JT: Insulin resistance induced by glucosamine in fructose-fed rats. Horm Metab Res 2009, 41:542-547.
  • Dostrovsky NR, Towheed TE, Hudson RW, Anastassiades TP: The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature. Osteoarthritis Cartilage 2011, 19:375-380.
  • Henrotin Y, Chevalier X, Herrero-Beaumont G, McAlindon T, Mobasheri A, Pavelka K, Schön C, Weinans H, Biesalski H. Physiological effects of oral glucosamine on joint health: current status and consensus on future research priorities. BMC Res Notes. 2013 Mar 26;6(1):115.
  • Kim E, Choi Y, Jang J, Park T. Carvacrol Protects against Hepatic Steatosis in Mice Fed a High-Fat Diet by Enhancing SIRT1-AMPK Signaling. Evid Based Complement Alternat Med. 2013;2013:290104.
  • Largo R, Alvarez-Soria MA, Diez-Ortego I, Calvo E, Sanchez-Pernaute O, Egido J, Herrero-Beaumont G:  Glucosamine inhibits IL-1beta-induced NFkappaB activation in human osteoarthritic chondrocytes. Osteoarthr Cartil. 2003, 11:290–298.  
  • Litten-Brown JC, Corson AM, Clarke L. Porcine models for the metabolic syndrome, digestive and bone disorders: a general overview. Animal. 2010 Jun;4(6):899-920.
  • Muniyappa R, Karne RJ, Hall G, Crandon SK, Bronstein JA, Ver MR, Hortin GL, Quon MJ. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes. 2006 Nov;55(11):3142-50.
  • Nakamura H, Masuko K, Yudoh K, Kato T, Kamada T, Kawahara T. Effects of glucosamine administration on patients with rheumatoid arthritis. Rheumatol Int. 2007 Jan;27(3):213-8.
  • Ostojic SM, Arsic M, Prodanovic S, Vukovic J, Zlatanovic M: Glucosamine administration in athletes: effects on recovery of acute knee injury. Res Sports Med. 2007; 15:113–124. 
  • Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH: Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007, 333:333-339.
  • Simon RR, Marks V, Leeds AR, Anderson JW. A comprehensive review of oral glucosamine use and effects on glucose metabolism in normal and diabetic individuals. Diabetes Metab Res Rev. 2011 Jan;27(1):14-27.
  • Spector TD, Harris PA, Hart DJ, Cicuttini FM, Nandra D, Etherington J, Wolman RL, Doyle DV. Risk of osteoarthritis associated with long-term weight-bearing sports: a radiologic survey of the hips and knees in female ex-athletes and population controls. Arthritis Rheum. 1996 Jun;39(6):988-95.
  • Yoshimura M, Sakamoto K, Tsuruta A, Yamamoto T, Ishida K, Yamaguchi H, Nagaoka I: Evaluation of the effect of glucosamine administration on biomarkers for cartilage and bone metabolism in soccer players. Int J Mol Med. 2009; 24:487–494.
  • Yoshimura M, Aoba Y, Naito K, Watari T, Murakami S, Yoshimura K, Nakagawa T, Yamamoto T, Yamaguchi H, Nagaoka I. Effect of a chicken comb extract-containing supplement on subclinical joint pain in collegiate soccer players. Exp Ther Med. 2012 Mar;3(3):457-462.