Tauroursodeoxycholic Acid (TUDCA) - Research Overview: Newly Appreciated Liver Protectant, Potential Antidiabetic, Thyroid Booster and a Heart- and Neuroprotective Agent!?

Image 1: If you decide to start your own TUDCA import/export company, make sure you get your supply from chemical sources in the Far East and not from a bear farm like this in the northern province of Quang Ninh, Vietnam, where bear bile is "harvested" and sold to tourists for $500+/20cc (TalkVietnam. 2012)

Last week's "On Very Short Notice" item on the ability of TUDCA, i.e. tauroursodeoxycholic acid to stimulate the conversion of the "inactive" thyroid hormone T4 to its active counterpart T3 has caused quite a stir and instigated questions related to appropriate dosages and other potential benefits of a previously largely overlooked bile acid. With the recent interest from "using" muscle heads looking to protect their liver and overall health, however, the demand for TUDCA appears to be so high that whichever source Nutraplanet, the only major retailer I know of that has been selling bulk TUDCA at a reasonable price, must have gotten overwhelmed. This and Fatfree's personal request are reason enough for me to compile a brief write-up that may provide you with some clues on whether or not it may be worth to look for alternative sources on the web or even start your own little TUDCA import/export business.

What is tauroursodeoxycholic acid aka TUDCA ?

Tauroursodeoxycholic acid is a bile acid also known as TUDCA formed in the liver by conjugation of deoxycholate with taurine, usually as the sodium salt. While Western medicine has only gotten wind of the anti-apoptotic effects and its ability to protect mitochondria from cellular elements that would otherwise interfere with energy production within the past 20 years, or so, bear bile - you guessed it, a natural source of TUDCA - has an over 3,000 yearlong history of being used to treat visual disorders (Boatright. 2006), if which we know today that many of them can be treated and prevented by the administration of TUDCA and other bile-acids or bile-acid precursors, such as taurine (click here to read all about taurine).

So what's the suggested dose? That's actually quite a tricky question, because the number of human studies can be counted on the fingers of one hand (and this is still an exaggeration) and the available rodent data is mostly based on studies where the TUDCA was injected into the peritoneal cavity, which - depending on the compound that is used - will usually yield a bioavailabilty that's higher than what you will see with oral ingestion of the compound, yet lower than from intravenous injections
All of the following values are calculated for an 80kg human using the standard HED formula and are based on rodent studies showing benefits for the respective organ:

• Heart - 650mg
• Diabetes - 975mg
• Liver - 400-3,200mg
• Alzheimer's - 4,000mg*
• Parkinson's - 350mg
• Pancreas -  3,250mg

* This is the only value that's based on oral administration for the others I simply assumed 1:1 bioavailability which is probably already an overestimation for the liver and certainly for other tissues, since part of the TUDCA probably won't survive the first pass through the liver.

The distinction between different bile acids is difficile and beyond the scope of this mini-overview. What all of them have in common is that they are physiological detergents that facilitate excretion, absorption, and transport of fats and sterols in the intestine and liver. Bile acids are also steroidal amphipathic molecules derived from the catabolism of cholesterol, which makes them the ideal partner for both "water" and "fat soluble" molecules and allows them to do their job as major modulators of lipid secretion, bile flow and the absorption of dietary fats and vitamins. Aside from these long-established functions their role as regulators of key enzymes involved not only in cholesterol homeostasis, but also whole energy homeostasis has attracted more and more interest over the last years. The unique detergent properties of bile acids are essential for the digestion and intestinal absorption of hydrophobic nutrients.

No effect without "side effect"!

Yet despite their metabolic utility bile acids have potent toxic properties and can - at high dosages - actually disrupt the very membranes they help to protext when they are administered at lower doses, therefore their accumulation in the blood and tissue is usually tightly regulated. And while Martinez-Diez et al. have shown that conjugated.bile acids have a very high toxicity threshold compared to their unconjugated cousins (Martinez-Diez. 2000), we are most probably still dealing with one of those classic U-shaped dose-response curves for TUDCA (with no effects at very low, beneficial effects at medium levels and toxicity issues at high levels) which are so ubiquitous in nature and still so difficult to understand for someone acculturated to the typical Western "more is more" mentality (Zinc would be another example, by the way; cf. "Zinc: 15mg is Plenty!").

A non-exhaustive list of proven benefits

• With its modulatory effects on the cell cylce regulator c-Jun N-terminal kinase (JNK), the generation and scavenging of radical oxigen specimen  and glutathione S-transferase (GST) activity, which is necessary for the masteroxidant glutathione to do its job, TUDCA effectively prevented / reduced neurodegenation in rodent model of Parkinson's disease (Castro-Caldas. 2012). It has also been shown to reduce the amyloid beta-induced synaptic toxicity that is so characteristic of Alzheimer's disease (Nunes. 2012; Ramalho. 2012)

• 

  Figure 1: Anti-inflammatory effect of TUDCA on FFA treated adipocytes; reduction in TNF-alpha and IL-6 (also vs. baseline; directly from Jia. 2011))

  Similar to taurine TUDCA appears to play an important role in cell osmolity, and has been shown to inhibit endoplasmic reticulum stress (ER) in embryonic development and ventricular contractile dsyfunction (malfunction of the heart) due to type II diabetes, fatty acid accumulation in the heart (Hua. 2010) and preserve cone density in the eye (Kim. 2012; Takada. 2012; Zhang. 2012a,b). 
• The same anti-ER mechanism also protects the insulin releasing pancreatic beta cells of Wistar rats (Lee. 2010; Tang. 2012) and the kidney (Gao. 2012) from damage due to increased blood glucose.  And Rivard et al. were even able to show that 400mg/kg of TUDCA, when they were administered intravenously were able to reduce apoptosis (death of hear cells) following myocardial infarction in rats (Rivard. 2007).
• TUDCA has also been shown to ameliorat insulin resistance in hypertrophic adipocytes (fat cells that burst from the seams; Jiao. 2011, Yoshizaki. 2012), to keep the expression of the adiponectine up (Zhou. 2010) and the inflammatory induced neovascularization in type II diabetes in check (Amin. 2012).  
• Despite the fact that TUDCA is also effective against endoplasmic rectilium stress in the liver and in skeletal muscle it cannot save a methionine and choline deficient liver from getting clogged with fat (Henkel. 2012), or a palmitate (a saturated fatty acid) treated myotube from becoming insulin resistant, (Rieusse. 2012). 
• What it can do, however is protect liver from apoptosis induced by natural or synthetic PPAR-gamma ligands (see "TTA + Fish Oil - Fat Burning Superfats or Hepatoxic Pro-Oxidants?" and "TTA + Fish Oil Revisited - Increased Intramuscular Omega-3 Levels Compromise Heart and Skeletal Muscle Performance"; cf. Nonaka. 2008) and ethanol-feeding (Colell. 2011)

• 

  Figure 2: Western blot analysis of influenza NP, NS1, and M1 proteins with corresponding densitometry displayed as averages with S.E. Proteins - reduced expression indicate a reduced replication rate (adapted from Hassan. 2011)

  Interestingly the same anti-ER effects that protect the heart, the pancreas, the kidneys and, in the presence of adequate choline and methionine, also the liver, will also inhibit influenza A viral replication (Hassan. 2012; in-vitro data)
• TUDCA has also been found to have antibacterial effects, or rather to prevent the cytotoxic effects of  Clostridium sordellii lethal toxin (CSLT) from virulent strains of Clostridium sordellii (Schulz. 2009) 

• Only when it's conjugated to taurine UDCA (then T + UDCA = TUDCA ;-) will promote hydrocholeresis or, put simply, the output of bile acid (Úriz. 2011; intravenous administration). In view of the emerging importance of bile acids in overall energy expenditure and thyroid function (Ockenga. 2012).
  This observation could well-explain the effects TUDCA has on the conversion of T4 => T3, which spiked your interest in the last installment of "On Short Notice", here at the SuppVersity (see "On Short Notice July 21, 2012").
• In this context it may also be wort mentioning that Nathanson et al. observed a direct stimulative effect of UDCA, the taurine devoid cousin of TUDCA on hepatic ATP secretion (Nathanson. 2001) and Drack et al. report that subcutaneous injections of 500 mg/kg in 0.15 M NaHCO₃ to obesity prone mice reduced their weight gain by -22%; a significant effects on "normal" mice could was yet not observed in the study (Drack. 2012). 

And what about humans?

As mentioned earlier, the number of studies in which TUDCA was actually administered to human beings is negligible and of actual relevance in the current context are probably on these two:

Figure 3: Effect of placebo or TUDCA on skeletal muscle insulin receptor substrate (IRS), Akt and JNK levels (Kars. 2010)

• Improved liver & muscle, but not adipose tissue insulin sensitivity in obese men and women (Kars. 2010) The main finding of this randomized double-blind study in which 20 obese subjects ([means +/- SD] aged 48 +/- 11 years, BMI 37 kg/m²) were assigned to receive either TUDCA at a dose of 1,750 mg/day or a placebo was a highly significant increase in insulin sensitivity (~30%; p < 0.05), which was - and this is would actually not be a bad thing for a physical culturist - liver and muscle specific!
  In combination with it's effect on the muscular and hepatic expression of p-AKT, this could make TUDCA the nutrient repartitioner (R-)ALA is not (cf. "Lean & Muscular with Alpha Lipoic Acid?"), if those effects would translate to individuals with normal insulin sensitivity (they do translate into human muscle cells in the Petri dish, which are protected against glucosamine induced decreases in GLUT-4 activity, when enough TUDCA was present in the incubation media; cf. Raciti. 2010).
• Surprisingly ineffective adjuvant after liver transplantation (Angelico. 1999) While you would expect that something that is good for liver health would also help as an adjuvant to the treatment of patients who received a liver transplant, the 16 subjects who were randomized to the active 2x250mg TUDCA treatment arm of the study did not see any statistically significant benefit in terms of one-year actuarial survival.

Although the latter of these studies may actually be somewhat disappointing, its results are actually quite educative - after all, they put another emphasis on something I have touched upon in numerous previous blogposts, already: Even in cases as the one at hand, where the presence of statistically reduced serum cholesterol levels (p < 0.02) and less exuberant cholestasis confirm that a certain compound, in  this case TUDCA, worked in vivo similarly to what it did in vitro, this does by no means implicate that it will also yield the real world results you would expect.

Image 2: Like the SuppVersity on Facebook and make sure you always get the latest news; this includes updates, links and comments on interesting articles around the web many of which are not even mentioned on the website - you don't want to miss those, do you?

Implications: The "negative" or rather NULL outcome of the study by Angelico et al. should have reminded you that you better display a healthy degree of skepticism towards all the previously presented "scientifically established" benefits of TUDCA. Neither I, nor any of the researchers (not even Kars et al.) should have the hubris to tell you that taking X amounts of tauroursodeoxycholic acid will save your liver from the toxic effects of oral anabolic steroids, will help you in your battle against diabesity or make a powerful ally in your quest for a leaner, more muscular physique. And still, this mini-review of the literature should have shown you that TUDCA has a lot of potential, future studies will yet have to confirm, for whom these potentials can actually be realized and what dosages of a hitherto pretty pricey supplement will be necessary to produce the desired results... Needless to say that the SuppVersity is going to be the place wheer you will read about these studies first- right?

References:

• Amin A, Choi SK, Galan M, Kassan M, Partyka M, Kadowitz P, Henrion D, Trebak M, Belmadani S, Matrougui K. Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice. J Pathol. 2012 Jun;227(2):165-74. 
• Boatright JH, Moring AG, McElroy C, Phillips MJ, Do VT, Chang B, Hawes NL, Boyd AP, Sidney SS, Stewart RE, Minear SC, Chaudhury R, Ciavatta VT, Rodrigues CM, Steer CJ, Nickerson JM, Pardue MT. Tool from ancient pharmacopoeia prevents vision loss. Mol Vis. 2006 Dec 29;12:1706-14. 
• Burroughs AK, Westaby D: Liver, biliary tract and pancreatic disease in Clinical Medicine, Eds. Kumar P, Clark M. Elsevier 2002
• Castro-Caldas M, Carvalho AN, Rodrigues E, Henderson CJ, Wolf CR, Rodrigues CM, Gama MJ. Tauroursodeoxycholic Acid Prevents MPTP-Induced Dopaminergic Cell Death in a Mouse Model of Parkinson's Disease. Mol Neurobiol. 2012 Jul 8.
• Chen Y, Liu CP, Xu KF, Mao XD, Lu YB, Fang L, Yang JW, Liu C. Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes. Am J Nephrol. 2008;28(6):1014-22. Epub 2008 Jul 23.
• Colell A, Coll O, García-Ruiz C, París R, Tiribelli C, Kaplowitz N, Fernández-Checa JC. Tauroursodeoxycholic acid protects hepatocytes from ethanol-fed rats against tumor necrosis factor-induced cell death by replenishing mitochondrial glutathione. Hepatology. 2001 Nov;34(5):964-71.
• Drack AV, Dumitrescu AV, Bhattarai S, Gratie D, Stone EM, Mullins R, Sheffield VC. TUDCA slows retinal degeneration in two different mouse models of retinitis pigmentosa and prevents obesity in Bardet-Biedl syndrome type 1 mice. Invest Ophthalmol Vis Sci. 2012 Jan 5;53(1):100-6.
• Gao X, Fu L, Xiao M, Xu C, Sun L, Zhang T, Zheng F, Mei C. The nephroprotective effect of tauroursodeoxycholic Acid on ischaemia/reperfusion-induced acute kidney injury by inhibiting endoplasmic reticulum stress. Basic Clin Pharmacol Toxicol. 2012 Jul;111(1):14-23.
• Hassan IH, Zhang MS, Powers LS, Shao JQ, Baltrusaitis J, Rutkowski DT, Legge K, Monick MM. Influenza A viral replication is blocked by inhibition of the inositol-requiring enzyme 1 (IRE1) stress pathway. J Biol Chem. 2012 Feb 10;287(7):4679-89. Epub 2011 Dec 22.
• Henkel AS, Dewey AM, Anderson KA, Olivares S, Green RM. Reducing endoplasmic reticulum stress does not improve steatohepatitis in mice fed a methionine- and choline-deficient diet. Am J Physiol Gastrointest Liver Physiol. 2012 Jul;303(1):G54-9. 
• Hua Y, Kandadi MR, Zhu M, Ren J, Sreejayan N. Tauroursodeoxycholic acid attenuates lipid accumulation in endoplasmic reticulum-stressed macrophages. J Cardiovasc Pharmacol. 2010 Jan;55(1):49-55. 
• Jiao P, Ma J, Feng B, Zhang H, Diehl JA, Chin YE, Yan W, Xu H. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKβ  pathways. Obesity (Silver Spring). 2011 Mar;19(3):483-91. 
• Lee YY, Hong SH, Lee YJ, Chung SS, Jung HS, Park SG, Park KS. Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress. Biochem Biophys Res Commun. 2010 Jul 9;397(4):735-9.
• Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010 Aug;59(8):1899-905.
• Kim JS, Song BS, Lee KS, Kim DH, Kim SU, Choo YK, Chang KT, Koo DB. Tauroursodeoxycholic Acid Enhances the Pre-Implantation Embryo Development by Reducing Apoptosis in Pigs. Reprod Domest Anim. 2011 Dec 13.
• Martinez-Diez MC, Serrano MA, Monte MJ, Marin JJ. Comparison of the effects of bile acids on cell viability and DNA synthesis by rat hepatocytes in primary culture. Biochim Biophys Acta. 2000 Feb 21;1500(2):153-60.
• Nathanson MH, Burgstahler AD, Masyuk A, Larusso NF. Stimulation of ATP secretion in the liver by therapeutic bile acids. Biochem J. 2001 Aug 15;358(Pt 1):1-5.
• Nonaka M, Tazuma S, Hyogo H, Kanno K, Chayama K. Cytoprotective effect of tauroursodeoxycholate on hepatocyte apoptosis induced by peroxisome proliferator-activated receptor gamma ligand. J Gastroenterol Hepatol. 2008 Jul;23(7 Pt 2):e198-206.
• Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D'Hooge R, Rodrigues CM. TUDCA, a Bile Acid, Attenuates Amyloid Precursor Protein Processing and Amyloid-β Deposition in APP/PS1 Mice. Mol Neurobiol. 2012 Jun;45(3):440-54. 
• Ockenga J, Valentini L, Schuetz T, Wohlgemuth F, Glaeser S, Omar A, Kasim E, duPlessis D, Featherstone K, Davis JR, Tietge UJ, Kroencke T, Biebermann H, Köhrle J, Brabant G. Plasma bile acids are associated with energy expenditure and thyroid function in humans. J Clin Endocrinol Metab. 2012 Feb;97(2):535-42.
• Ramalho RM, Nunes AF, Dias RB, Amaral JD, Lo AC, D'Hooge R, Sebastião AM,  Rodrigues CM. Tauroursodeoxycholic acid suppresses amyloid β-induced synaptic  toxicity in vitro and in APP/PS1 mice. Neurobiol Aging. 2012 May 21.
• Rieusset J, Chauvin MA, Durand A, Bravard A, Laugerette F, Michalski MC, Vidal H. Reduction of endoplasmic reticulum stress using chemical chaperones or Grp78 overexpression does not protect muscle cells from palmitate-induced insulin resistance. Biochem Biophys Res Commun. 2012 Jan 6;417(1):439-45. 
• Sokol RJ, Dahl R, Devereaux MW, Yerushalmi B, Kobak GE, Gumpricht E. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J Pediatr Gastroenterol Nutr. 2005 Aug;41(2):235-43.
• Takada A, Miki T, Kuno A, Kouzu H, Sunaga D, Itoh T, Tanno M, Yano T, Sato T, Ishikawa S, Miura T. Role of ER Stress in Ventricular Contractile Dysfunction in  Type 2 Diabetes. PLoS One. 2012;7(6):e39893. Epub 2012 Jun 29.
• Tang C, Koulajian K, Schuiki I, Zhang L, Desai T, Ivovic A, Wang P, Robson-Doucette C, Wheeler MB, Minassian B, Volchuk A, Giacca A. Glucose-induced  beta cell dysfunction in vivo in rats: link between oxidative stress and endoplasmic reticulum stress. Diabetologia. 2012 May;55(5):1366-79.
• Úriz M, Sáez E, Prieto J, Medina JF, Banales JM. Ursodeoxycholic acid is conjugated with taurine to promote secretin-stimulated biliary hydrocholeresis in the normal rat. PLoS One. 2011;6(12):e28717. Epub 2011 Dec 14. 
• Raciti GA, Iadicicco C, Ulianich L, Vind BF, Gaster M, Andreozzi F, Longo M, Teperino R, Ungaro P, Di Jeso B, Formisano P, Beguinot F, Miele C. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells.
  Diabetologia. 2010 May;53(5):955-65. 
• Rivard AL, Steer CJ, Kren BT, Rodrigues CM, Castro RE, Bianco RW, Low WC.  Administration of tauroursodeoxycholic acid (TUDCA) reduces apoptosis following myocardial infarction in rat. Am J Chin Med. 2007;35(2):279-95. 
• Schulz F, Just I, Genth H. Prevention of Clostridium sordellii lethal toxin-induced apoptotic cell death by tauroursodeoxycholic acid. Biochemistry. 2009 Sep 29;48(38):9002-10.
• TalkVietnam. Bear bile tourism thrives despite exposés. April 5, 2012 at 12:30 pm. < http://talkvietnam.com/2012/04/bear-bile-tourism-thrives-despite-exposes/ > retrieved July 27, 2012
• Yoshizaki T, Kusunoki C, Kondo M, Yasuda M, Kume S, Morino K, Sekine O, Ugi S, Uzu T, Nishio Y, Kashiwagi A, Maegawa H. Autophagy regulates inflammation in adipocytes. Biochem Biophys Res Commun. 2012 Jan 6;417(1):352-7. 
• Zhang T, Baehr W, Fu Y. Chemical Chaperone TUDCA Preserves Cone Photoreceptors in a Mouse Model of Leber Congenital Amaurosis. Invest Ophthalmol Vis Sci. 2012a Jun 5;53(7):3349-56.
• Zhang JY, Diao YF, Kim HR, Jin DI. Inhibition of endoplasmic reticulum stress improves mouse embryo development. PLoS One. 2012b;7(7):e40433. Epub 2012 Jul 13. 
• Zhou L, Liu M, Zhang J, Chen H, Dong LQ, Liu F. DsbA-L alleviates endoplasmic reticulum stress-induced adiponectin downregulation. Diabetes. 2010 Nov;59(11):2809-16

On Short Notice: Testosterone - 12% Drop /W 75g Glucose? Fat Loss - Adzuki, Leucine + B6 or HiMaize? Thyroid - T3↓ + rT3↑, Is Blood Sugar to Blame and Can TUDCA Help? +More!

Image 1: It's quite funny, I am piling up so many of these interesting mini-news that I actually had to drop a few or postpone them to next week to keep the size of this post manageable without a direct brain transmission device like the one you see in this picture ;-)

"On short notice" is the name of the new 'saturdaily' SuppVersity column and therefore I will try to make it short: After all, you've got a hell lot to learn today and unless you have just crawled out from beneath your sheets, your testestorone levels and with it your cognitive abilities will aready have declined - that's not you? Well I guess you have the hubris of a boxer, then, or you did simply sleep so little that even your increased energy consumption could not make up for the memory dysfuction that's been brought about by the sleep deficit. Let's just hope that your cell mass is at least so high that your basal energy expenditure is sufficient to burn those serotonergic carb binges off, because I am pretty sure that the leucine + B6 combo from NuSirt Science won't do that for you... what? You don't understand a word? Don't worry, you will, once you are done with today's installment of "On Short Notice"...

Adzuki bean extract - just another fat binder or more?

Image 2: Those Adzuki beans look pretty much like kidney beans, don't they? Ah, btw. you did know that kidney beans contain a "carb blocker" (a molecule that hampers carbohydrate digestion; cf. Mosa. 2008) - did you?

I am really no a fan of those "anti-fat absorption agents", as most of them will have immediate or long-term consequences on your supply of fat soluble nutrients which could in fact be worse for your overall health than the few additional lbs of body fat you may be carrying around. That being said, you may still be interested in the latest results from Tomoko Kitano-Okada and his colleagues from the Department of Food Science, Obihiro University of Agriculture and Veterinary Medicine in Inadacho, Obihiro, Hokkaido, Japan. In a combined in-vivo (rodent) and in-vitro study, the researchers found that control and high fat diets with 1% adzuki bean extract, despite having only non-significant effects on the high fat diet (HFF) induced weight gain, did not just ameliorate the HFD induced deteriorations in serum low-density lipoprotein (LDL) and triglyceride (TRIG) levels, but lead to marked improvements in LDL and TRIG in the rodents on the standard diet (55% cornstarch + 10% succrose, 20% casein, 5% soybean oil), as well.

Figure 1: Absolute total cholesterol and triglyceride levels, as well relative (expressed in percent of respective values for animals on control diet) liver and faecal matter weight and lipid content in male Fischer rats after 4 weeks on control (high carb) or high fat diets (data based on Kitano-Okada. 2012)

This is interesting as it appears to confirm the hypothesis that the Adzuki beans do not work their anti-hyperlipidemic (=cholesterol and triglyceride lowering) effects solely via their ability to increase the fat content of the excrements, but also via other mechanisms of which Kitano-Okada et al. identified the reduction of inflammatory cytokines (e.g. 24–51% IL-6 reduction following treatment with Adzuki bean extract containing polymerised polyphenols) and the likewise dose-dependent profound reduction in glycerol-3-phosphate dehydrogenase, an enzyme that is necessary to generate glycerol (fatty acids) from carbohydrates, in in-vitro cell studies with human adipocytes by up to -50%!

Implications: Just in case you are now interested in popping some of those beans you should be aware that the product that was used in the study contained 16% polyphenols (including 470 mg anthocyanidins, 20.7 mg catechins, 2.33 mg caffeic acid, 2.62 mg ferulic acid, 44.5 mg quercetin, and 102 mg protocatechuic acid), that the human dose equivalent would ~5-6g /day and that you should try to get an extract with polymerized (=interconnected) phenols, as those were roughly 2x more active in the in-vitro essays (although it is questionably if this translates into better real world results).

Marathon running is for the metabolically efficient!

Image 3: Marathoners have nothing to lose!

Just in case you have ever wondered what makes a good marathon runner a very good marathon runner, the results of a study that was published in the latest issue of Sport Sciences for Health could hold the answer: Marathon champions have a surprisingly high metabolic efficiency (Andreoli. 2012), or put more simply, they are carrying little to no (for their goals!) useless ballast like profane fast-twitch muscle fibers and only so much fat as it takes to optimally protect their organs (in percentages this is yet still way more than the guys with the "profane" fast-twitch fibers are carrying around)

As the data in figure 2 goes to show, their body cell mass (BCM), a more accurate measure of the amount of metabolically active tissue in their body than "lean mass" (Moore. 1963), is about equal to the one of division 1 football players (data compiled from Andreoli. 2003 and Andreoli. 2012), but their lean mass is much lower (as mentioned before they have no use for heavy type I and type IIX muscle fibers).

Figure 2: Body composition data (fat free  mass, body cell mass, body fat percentage) in different athletes and control (left), as well as correlation between BCMI (BCM / height) with marathon running time (right; data compiled from Andreoli. 2003 and Andreoli. 2012)

In conjunction with higher metabolic rates, of which Andreoli et al. found that they are the 2nd best predictor of marathon times (correlation r = -0.69 vs. BCMI = BCM / height with r = -0.73), a high amount of "oxygen-exchanging, potassium-rich, glucose-oxidizing, work-performing cells" (=what the BCM measures ;-) and correspondingly high resting energy expenditures (r = 0.77) do thus make the difference between victory and defeat.

Sounds strange, when you come to think about it - right? "People with higher energy expenditures make good marathon runners?" Well, I guess you better think of it differently: Bigger engines need more fuel and as we have seen yesterday, a very welcome side effect of "mitochondrial biogenesis that's induced by Chitooligosaccharide supplementaton" was an increase in endurance - that those big engines have to be fueled adequately, by the way, does also explain why people like Michael Phelps do in fact have to eat like a horse - that he really needs 12,000-15,000 calories per day is yet probably just another of those urban legends.

Implications: Interestingly enough, the necessity of having a "big engine" (=huge metabolically active cell mass) does also implicate that the formerly obese, who appear to flock around marathon or at least endurance running, with their slabs of metabolically unactive tissue and suppressed metabolic rates due to months or years of undereating and overtraining have little to no chance of ever winning a marathon race, which  - and this may be the most surprising finding of the study - is not the prerogative of the person who "burns the less fuel"  - at least not as long as nobody takes away their 30 bananas a day and the highly concentrated energy gels marathoners use on their 42-km run, I guess ;-)

Can 75g of Glucose Reduce Testosterone by 10% Within Minutes?

In a recently conducted trial, Lisa M. Caronia and her colleagues from the Massachusetts General Hospital in Boston observed an astonishing -12% drop in total testosterone within 30 min of the ingestion of an 75g of glucose - the same amount you would ingest in every regular oral glucose tolerance test (OGTT) and even less than some hilarious "expert suggestions" will tell you would need to optimally replenishing your allegedly depleted glycogen stores after an intense workout.

Figure 3: Glucose, insulin, SHBG, lepin, LH and testosterone levels in response to the oral ingestion of 75g glucose in 74 young men; data expressed relative to baseline (data adapted from Caroni. 2012)

If you take a closer look at the exact data in figure 3 you will probably be as startled with respect to the underlying mechanism behind this reduction as the researchers were. Aside from the drop in testosterone, the only statistically significant changes (indicated by * in figure 3) the scientists observed, were a profound drop in leptin and the explosive increase in glucose and insulin - both of which, the decrease in leptin and the increase in insulin, have yet been shown to augment testosterone production in previous studies (Adashi. 1982; Giovambattista. 2003). At least with respect to the drop in leptin, Caronia et al. do yet point out, that it could be a mere conseqence of "circadian fluctuations in leptin that are unrelated to glucose administration" (Caronia. 2012; those fluctuations, by the way, have been observed by e.g. Panarotto. 1999)

Symptoms of low Testosterone

• Lean muscle loss, agitation/motor dyskinesia, decreased appetite
• Depression, guilt, low-self esteem, anhedonia, decreased cognitive capacity
• Increased stress, general fatigue, sleep disturbances
• Decreased libido, decreased spontaneous erections, decreased ejaculate, erection dysfunction, decreased sexual fantasies, anorgasmia

Furthermore, neither cortisol (not shown in figure 3), a potential suppressor of testicular testosterone production, nor luteinizing hormone (LH), which stimulates testicular testosterone production and should actually increase in response to the drop in testosterone, did budge in the course of the 120 min after the 74 men (age range: 19-74 years, mean: 51.4 ± 1.4) who reported to the lab after a 12-hour overnight fast had ingested the 75g of glucose.

As Caronia et al. point out, the non-existent response of the luteinizing hormone (LH) levels to the reduced testosterone levels, is probably the only clue we have as far as the underlying mechanism of allegedly glucose-induced reduction in testosterone levels is concerned, because "one would anticipate that the decreased negative feedback of T would lead to increased LH levels" (Caronia. 2012). And though Caronia et al. are certainly right that this and the fact that this was not the case and that the effect occured in healthy, in insulin resistant and in diabetic subjects (where it was slightly more pronounced, though; data not shown), clearly "suggests an additional central component", the latter should actually, as it was observed by  Iranmanesh et al. only recently involve a drop in luteinizing hormone (Iranmanesh. 2012).

After thinking about that for a couple of minutes I was just about to write in the implications that this would be another good reason not to go overboard on fast carbs, when I remembered my previous research on all things testosterone for the "Intermittent Thoughts on Building Muscle" Series and what the scientists themselves had said about the declining leptin levels - well, let's take a look at what the testosterone levels of both young and old men do between 8:00am and 12:00pm, i.e. during the exact time the subjects in the Caronia study ingested their allegedly anti-androgenic bolus of 75g of glucose:

Figure 4: An analysis of the natural diurnal testosterone rhythm in young men (dotted line in graph in the background; Diver. 2003) reveals that the "drop" in testosterone in response to the OGT is likely only a consequence of the pronounced diurnal rhythmicity of the total testosterone levels - in older men we see the exact same phenomenon, but the effect is about 50% less pronounced.

The data from the Diver study in figure 4 does not leave a slight doubt that the OGTT, or rather the 75g of glucose the subject had to consume probably had no independent effect on the level of testosterone and that the decline Caronia et al. observed is simple a result of the natural diurnal rhythm. This does not exclude that the latter is per se connected to food intake as the availability / influx of energy is, beside light, probably, the most important setscrew for our clock-genes.

Image 4: Conclusions are rarely 100% conclusive.

Implications: There are actually two important take home messages from this study and "carbs are so bad for you" is not one of them:

1. draw your own conclusions, and don't trust those of others blindly regardless of their "credentials"
2. make sure that you don't ignore the diurnal rhythmicity of testosterone, and are thus fooled to believe that short term changes in the +/- 50% range would make you build or lose muscle, let alone your virility

The second take home message is also of great importance when you test your own testosterone levels and/or read about the testosterne boosting magic of the latest supplement scam (aka "natural testosterone booster"). As you can see, you can easily achieve a  70-80% increase or decrease in testosterone by simply measuring at different points in the day.

On Very Short Notice

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  Figure 5: Changes in fatty acid metabolism (top) and inflammatory markers (bottom) in response to 4 weeks of thrice daily NuFit (250mg leucine + 30mg vitamin B6) supplementation to 20 obese men and women (based on Zemel. 2012)

  Astonishing improvements in RQ & fatty acid oxidation from 2g of leucine and 30mg vitamin B6 - Although you need to be somewhat cautious with a study that was financed by NuSirt Sciences the producer of the 750mg leucine + 10mg pyridoxin supplement under scrutiny (Zemel. 2012), the effect the ingestion of those caps had on the fatty acid metabolism and moreover the expression of inflammatory markers in 20 overweight or obese subjects was literally marvelous (I leave the interpreation of this term up to you ;-). A decrease in respiratory quotient (=greater fatty acid, lower glucose oxidation), an increase in total fatty oxidation per day and more importantly and probably causally the decreases in TNF-alpha and CRP are changes I would not have expected to see within 4 weeks on 2.25g of leucine and 30mg of vitamin B6. After all,  you should see similar effects with almost every cheap (or expensive) BCAA supplement on the market - aside from even greater amounts of leucine most of them contain at least 10mg of additional B6.
• Fat burning machines can't have orange juice for breakfast - The additional 210kcal the subjects of a 2012 trial by scientists from the Children’s Hospital Oakland Research Institute consumed in form of "healthy" orange juice were not just more or less empty calories, they also reduced the postprandial fatty acid oxidation by whopping 25%. This lead Stookey et al. conclude that "independent of a state of energy excess, [drinking] a caloric beverage instead of drinking water with a meal [will decrease] the amount of fat consumed in the meal before their next meal." (Stookey, 2012) If you want to become / stay a fat burning machine (and in my humble opinion even if you just want to stay lean and healthy) you better eat your fruit and never drink it (let alone other caloric beverages, see "Fat content per Energy Drink 0g, Fat Gain Per Energy Drink 16g").

• 

  Image 5: The first hit on google says HiMaize will cost 8$/340mg; mimicking the dosage used in the study would thus be ~1$ per day; relatively cheap if you consider that it is not necessary a supplement, but can also be used for baking & co

  Resistant starch could stop and reverse developing diabetes - scientists from the University of Surrey and the venerable Imperial College in London were able to show that their 12 overweight (BMI 28.2±0.4 kg/m2) prodiabetic subjects' first-phase insulin secretion, which is the one that determines whether you do or don't go hyperglycemic right after the ingestion of a meal, by improved by ~35% after only 4 weeks of consuming a mildly resistant (60% resistant / 40% digestible) maize starch. Probably as a direct result of this early pro-insulinogenic effect, the HiMaize260 RS2 starch produced a -10% reduction in fasting blood glucose, compared to a regular tapioca starch of which the subjects in the control group consumed only 27g to assure that they would ingest equal amounts of glucose (Bodinham. 2012).
  Despite the fact that WM HDP is an artificial restistant starch, of which even less will be digested and absorbed as glucose in the small intestine, these results do confirm what we have already seen in the WM HDP studies and what some of the latest blogposts bordering on dietary fiber have hinted at, as well (e.g."Weightloss Threesome"): The effects of these not, or only partially digestible fibers and carbohydrates go way beyond simply filling you up or being non-insulinogenic (=not causing an insulin spike as even the low GI starches do). There is however, as Carolin L. Bodinham and her colleagues rightly point out, need for "further studies [...] to confirm these findings and to elucidate the mechanisms" and, as I would add, to identify whether or not this could work for people who have already developed type II diabetes, as well.
• Counter-intuitive effects of high glucose-dependent insulinotropic polypeptide (GIP) levels in form of increased insulin and reduced obesity: While the hitherto published studies on WM HDP (see previous bullet point) clearly suggest that part of its fatburning effect is mediated by a reduced, even almost non-existant GIP (and subsequently insulin response), a recent study from Canada clearly suggest that whenever you do consume regular starch a more pronounced incretin response will not just avoid hyperglycemia (due to the more pronounced release of insulin from the pancreas), but also improve / prevent adipose tissue inflammation, hepatic steatosis (non-alcoholic fatty liver disease) and even weight gain - remember: we are talking about higher insulin responses, here (Kim. 2012)! Unfortunately, the anti-obesity effect Su-Jin Kim and his colleagues observed in their experiments with GIP-overexpressing rodents, were mostly a direct consequence of reduced energy intakes and that those hardly ever translate into the real world is something I believe I don't have to tell you, right?

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  Figure 6: If your body does not convert T4 into T3 adequately taking levothyroxin (T4) may even worsen many of the symptoms of hypothyroidism due to increased conversion to r-T3 and an even more sluggish metabolism that certainly won't help to get blood glucose back under control (see also "Natural Thyroid Treatment with food")

  Low T3 syndrome (pseudo-hypothyroidism) or diabetes? This is an "oldie, but goldie", i.e. a study I happen on while doing research on this and that... in this case I do not even really know how this study appeared on my radar, but according to Kabadi et al. high blood sugar in type II diabetes does reduce the conversion of the "inactive" form of thyroid hormone, T4, to its active cousin, T3 and increases the conversion of T4 to rT3 (reverse T3). The latter is believed to act similar to a receptor blocker, which hinders T3 do to its metabollically activating job. The statistically highly significant (p < 0.0001) correlation (r = 0.611) the scientists observed between rT3 and fasting blood glucose would suggest that improper blood glucose management could be the root course of the heavily lamented high rT3 levels of thousands of posters on various bulletin boards all across the Internet (Kabadi. 1982). Now, the good news is that the researcher found that by controlling blood glucose levels you can return your rT3 and T3 levels back into the normal zone. 
• Tauroursodeoxycholic (TUDCA) and 4-phenylbutyric (4-PBA) increase T4 to T3 conversion - The chemical chaperones TUDCA and 4-PBA, of which the former has as of late been hailed as the new "milk thistle", i.e. the go-to-supplement for liver health among athletes who use oral anabolic steroids, could turn out to be a valuable tool not just to escape from the aforementioned vicious circle of low T3 and high rT3 levels, but also as a means to kickstart your metabolism. Although this hypothesis is based on data from a combined in-vitro + in-vivo rodent study (da-Silva. 2011), the shift away from glucose and towards fatty acid oxidation, as well as the doubled activity of the fat burning brown fat and the profound improvements in glucose tolerance, da-Silva et al. observed in their high-fat fed rodents certainly won't harm your physique.

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  Figure 7: Narcicistic personality traits of kickboxers, freestyle and  Greek Roman wrestlers, Boxers and Weightlifters (based on Tazegül . 2012)

  Weight lifters and boxer are the most narcissistic athletes - At least among the five groups the Turkish scientist Ünsal Tazegül analyzed for his recently published paper, the 17-19-year old male boxers and weight lifters had the most pronounced narcissistic character traits. While the boxers were the most exhibitionists and pretentious, the weight lifters were the most rebellious, inadaptable, spiteful, disrespecting (subsumed under exploitation) and ambitious, power-thirsty and spiteful among the subjects who participated in this study. Interestingly enough, the freestyle wrestlers appeared to be the guys with whom you would probably get along best. So what does that tell you? Nothing... and that's why this study is only on very short notice ;-)
• If you don't sleep yourself smart, you got to binge yourself half-smart: Just in case you have already forgotten what you read a few paragraphs above, the reason could be sleep deprivation. And while cognitive deficits due to sleep deprivation is nothing essentially new, another thing, namely the effectivity of increased daytime energy intake to recover your mental capacity, is something a recent study by Nina Herzog et al. has investigated for the first time (Herzog. 2012). Unfortunately, binging rescues only the procedural part of your memory (where you store how to brush your teeth before you go to bed ;-), it will not compensate for the detrimental effects a lack of adequate sleep will have on your declarative memory. If you also  take into account that it is going to make you fat and sick, I would thus suggest you go to bed now, after all you havale already done the single most important thing of the day - you've gotten your daily dose of SuppVersity news! And let's be honest, you don't want to forget any of these valuable lessons, do you ;-)

References:

1. Adashi EY, Fabics C, Hsueh AJ. Insulin augmentation of testosterone production in a primary culture of rat testicular cells. Biol Reprod. 1982 Mar;26(2):270-80.
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3. Andreoli A, Marfe G, Manzi V, Sinibaldi-Salimei P. Is body cell mass a predictive index of performance in male recreational long-distance runners? Sport Sci Health. 2012; 8:47–50
4. Bodinham CL, Smith L, Wright J, Frost GS, Robertson MD (2012) Dietary Fibre Improves First-phase Insulin Secretion in Overweight Individuals. PLoS ONE 7(7): e40834.
5. Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol (Oxf). 2003 Jun;58(6):710-7.
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10. Kim S-J, Nian C, Karunakaran S, Clee SM, Isales CM, et al. (2012) GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis. PLoS ONE 7(7): e40156.
11. Kitano-Okada T, Ito A, Koide A, Nakamura Y, Han KH, Shimada K, Sasaki K, Ohba K, Sibayama S, Fukushima M. Anti-obesity role of adzuki bean extract containing polyphenols: in vivo and in vitro effects. J Sci Food Agric. 2012 Apr 11.
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13. Mosca M, Boniglia C, Carratù B, Giammarioli S, Nera V, Sanzini E. Determination of alpha-amylase inhibitor activity of phaseolamin from kidney bean (Phaseolus vulgaris) in dietary supplements by HPAEC-PAD. Anal Chim Acta. 2008 Jun 9;617(1-2):192-5. Epub 2008 Feb 1. 
14. Panarotto D, Maheux P. Reduction of plasma leptin during a short-term fast, an oral glucose tolerance or a meal test can be a misleading bias in clinical studies. Diabetologia. 1999 May;42(5):634.
15. da-Silva WS, Ribich S, Arrojo e Drigo R, Castillo M, Patti ME, Bianco AC. The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure. FEBS Lett. 2011 Feb 4;585(3):539-44.
16. Stookey JD, Hamer J, Espinoza G, Higa A, Ng Vivian, Tinjero-Deck L, Havel PJ, King JC. Supplement: 2nd Forum on Child Obesity Interventions: Orange Juice Limits Postprandial Fat Oxidation after Breakfast in Normal-Weight Adolescents and Adults Adv Nutr July 2012.
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18. Zemel, M.B.; Bruckbauer, A. Effects of a Leucine and Pyridoxine-Containing Nutraceutical on Fat Oxidation, and Oxidative and Inflammatory Stress in Overweight and Obese Subjects. Nutrients 2012, 4, 529-541.