Less Than 15mg of DHEA Exert Identical Beneficial Effects on Insulin Sensitivity as 1h of Cardio 5x Per Week. Both Effects Mediated Via Increases in Intra-Muscular DHT

Image 1: It has long been established that diabetics have particularly low DHEA levels (Loviselli. 1994), but what's the chicken and what's the egg here?

It is quite funny, sometimes you don't hear about certain supplements, (pro-)hormones, exercise-modalities etc. in years and then, all of a sudden, there are two studies on the respective topic in one week; and moreover, two pretty interesting ones! Last Friday, exactly 7 days ago, you've read here at the SuppVersity about the muscle-protective effects of low-dose dehydroepiandrosterone (DHEA) supplementation during a 5-day intense multiple-type exercise protocol (cf. "DHEA Blunts Muscle Damage During 5 Days of Combined Endurance, Strength and HIIT Training in Young Men"). Today, I have another interesting set of data for you - data which could not just shed some light onto the underlying mechanisms of the said protective effects against skeletal muscle damage, but also on DHEA's beneficial effects on insulin sensitivity.

Not younger, but leaner with a minimalist dose of DHEA?

In a 6 week trial, and thus over a more than eight times longer timespan than in the previously mentioned human study on skelatal muscle damage, Koji Sato and his (or her?) colleagues from the Ritsumeikan University, the Senshu University and the University of Tsukuba (all in Japan, as you probably already suspected) investigated the effects a low dose of DHEA (human equivalent: 0.16mg/kg per day => 10-15mg/day) supplementation on the insulin, QUICKI (=quantitative insulin-sensitivity check index) and intramuscular DHEA and DHT (dihydrotestosterone) levels in sedentary or exercised dietary obese male rodents.

Figure 1: Relative insulin levels, QUICKI, intramuscular DHEA and DHT content in obese male rodents after 6 weeks of DHEA or combined DHEA + exercise (1h, 5days/week) treatment (data adapted from Sato. 2013)

As you can see in figure 1 the effects of both 5x/week running on a treadmill (ETA: 1h) and orally administered DHEA were profound. If you compare the "exercise only" group (red) to the two DHEA groups (green and violet), you will yet notice interesting parallels. Not only were the decreases in serum insulin and the increases (=improvements of insulin sensitivity) in the QUICKI test very similar, the exercise regimen alone yielded a +56% increase skeletal muscle DHEA content and a +71% increase in DHT.

Exercise increases intramuscular DHEA & DHT...
 

Figure 2: Hormonal cascade from DHEA to DHT; all enzymatic conversions can take place on a systemic and intra-cellular level!)

At least the latter, i.e. the increase in DHT should not be news to you if you have been following the in-depth articles at SuppVersity over the past couple of months. From the Intermittent Thoughts on DHT you know that exercise in general and HIT endurance exercise in particular has been found to boost intramuscular dihydrotestosterone levels, as well. The bros, or friends of bros among you, will probably also have heard the horrific stories about creatine monohydrate leading to increased levels of DHT (van der Merve. 2009), of which every reasonable person must actually assume that they are nothing but a downstream effect of increased training loads and/or improved adaptation... I mean, think about it "paleo style": Why would the mammalian body (rodent and human appear to react alike here) increase the DHEA and, via 5-alpha reductase (cf. figure 2), the dihydrotestosterone levels in response to high volume exercise, if not as a means of adaptation?

Oral DHEA + exercise = double-whammy against obesity

The combined treatment, or I should say the exogenous support of the exercise induced changes had - and this is not visible from the data in figure 1, astonishingly profound effects on the diet induced weight gain of the lab animals. While all other rodents became fatter, those in the exercise + DHEA group remained at a steady body weight level; an observation the researchers comment as follows:

Although DHEA administration and exercise training each produced beneficial effects, 6-weeks of combination treatment were more effective for obesity. The precise mechanisms that reduced abdominal fat weight in the combination group remain unclear, yet we can propose several plausible hypotheses. 2 weeks of DHEA administration has been shown to activate fatty acid metabolism-related enzymes, such as long-chain fatty acyl-coenzyme A synthase, and to increase free CoA levels in liver (Mohan. 1998; Mohan. 1990). In addition, exercise training is  known to reduce adipogenesis via upregulation of fatty acid metabolism and increased energy expenditure (Hou. 2003). Therefore, 6-weeks of combination treatment may have promoted additive reductions in abdominal fat volume.

In other words, while DHEA increases the efficacy of fatty acid oxidation, exercise takes care of the increase in energy expenditure which is - all convictions wrt to "calories don't count" and the "calories in vs. calories out"-hypothesis aside - still a fundamental prerequisite that the fatty acids do actually get burned and are not released into circulation to be restored or replaced a couple of hours later.

"Ok, I am just ordering some DHEA, how much should I take?"

Before you head over to the online vendor of your choice to make sure you get your share of DHEA before the FDA hears that it could hamper the sales of diabetes drugs and removes it from the OTC market, I would like to remind you that despite the fact that Sato et al. rightly claim that a "combination treatment [with DHEA and DHT] may be more beneficial than either therapy alone", a cursory glance on the data in figure 1 should suffice to tell you that those additional benefits as statistically significant as they may be are just that "additional" and that exercise alone yielded about equal results, is free of negative and full of beneficial side effects (update: as long as you don't overtrain; thanks Stapedius for this important note) and does not have the same host of studies refuting its efficacy as DHEA has (Clore. 1995).

It is nevertheless intriguing that a hormone the medical orthodoxy has, more or less all of a sudden, dropped like a hot potato and declared "questionable" and "ineffective" is now, roughly 15-20 years being rediscovered... and I am pretty sure that this was not the last DHEA study you will see and read about here at the SuppVersity ;-)

References:

1. Clore JN. Dehydroepiandrosterone and body fat. Obes Res. 1995 Nov;3 Suppl 4:613S-616S. Review.
2. Hou CW, Chou SW, Ho HY, Lee WC, Lin CH, Kuo CH. Interactive effect of exercise training and growth hormone administration on glucose tolerance and muscle GLUT4 protein expression in rats. J Biomed Sci. 2003 Nov-Dec;10(6 Pt 2):689-96.
3. Loviselli A, Pisanu P, Cossu E, Caradonna A, Massa GM, Cirillo R, Balestrieri A. [Low levels of dehydroepiandrosterone sulfate in adult males with insulin-dependent diabetes mellitus]. Minerva Endocrinol. 1994 Sep;19(3):113-9.
4. van der Merwe J, Brooks NE, Myburgh KH. Three weeks of creatine monohydrate  supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clin J Sport Med. 2009 Sep;19(5):399-404.
5. Mohan PF, Cleary MP. Effect of short-term DHEA administration on liver metabolism of lean and obese rats. Am J Physiol. 1988 Jul;255(1 Pt 1):E1-8.
6. Mohan PF, Ihnen JS, Levin BE, Cleary MP. Effects of dehydroepiandrosterone treatment in rats with diet-induced obesity. J Nutr. 1990 Sep;120(9):1103-14.
7. Sato K, Iemitsu M, Aizawa K, Ajisaka R. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab. 2008 May;294(5):E961-8. Epub 2008 Mar 18.
8. Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S. DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab (Lond). 2013 May 30;9(1):47. [Epub ahead of print]

Anti-Creatine β-Guanidinopropionic Acid (GPA) Increases AMPK, Decreases Blood Glucose & Insulin, Induces Weight loss Without Dieting, Increases Oxidative Capacity and Can Even Delay the Development of Mammary Cancer! BUT...

While he may be so fast that he is almost out of the focus, when the photographer finally released the shutter, Usain Bolt, the fasted man on earth actually doesn't look as if his fiber type composition was highly type II dominant, does he? 

While the relation may be distant, you will soon see that today's blogpost is somewhat related to Saturday's news item about the ability of high dose nicotinic acid to shift the muscle fiber type composition from a towards the oxidative side of things. After all, there is hardly anything that is more "glycolytic" (I am using the word here in a very broad sense) than the use of the intramuscular phosphocreatine stores to squeeze out another rep or explode out of the starting block and sprint towards the finish line in less than 10 seconds.

Ah, yes those phosphocreatine stores, they are great and creatine is the staple supplement for anyone looking to improve his glycolytic performance. But hey, wait a minute: Shouldn't that actually mean that taking creatine would be a bad thing for an ironman (not the one from the cinema, but the Hawaiian ;-)?

GPA - Supplemental creatine unloading for edurance athletes!?

Well, the answer to the question "Is creatine bad for endurance athletes" is, as long as you stick to reasonable doses "No! It isn't.". It neither helps nor hinders endurance performance and a "real" Ironman could probably even get away with one of those sugar-laden "cell-volumizers" without doing much harm. His body is would just burn through the carbs without any of them ending up as additional ballast on his hips. That said, previous studies by Vanakoski et al. or Chwalbiñska-Moneta clearly show that performance detriments are not an issue and in the latter of the two studies, the creatine supplement did even improve the "endurance (expressed by the individual lactate threshold) and anaerobic performance, independent of the effect of intensive endurance training" so that the highly trained rowers who participated in the study at hand would in fact have had an edge at the end of the race and may - if they would have otherwise been on par with the competition - probably have won the race (Vanakoski. 1998; Chwalbiñska-Moneta. 2003).

Surprise: Anyone of you who has ever taken NO Xplode 2.0 (new or old formula) has already been supplementing with GPA - both the original and the "advanced strength" formula contain an undisclosed amount of GPA. Apropos, if you are interested in the differences between the two, check out my previous article on the matter - I guess I don't give away too much, when I tell you that they are few and far between.

There is however a significant difference between not supplementing with creatine and relying on your own body's ability to produce the "meat amino acid" ("creatine" is derived from the greek word for meat) from L-arginine, glycine, and L-methionine and using a "supplement", or rather, another amino acid that does actually hamper its recycling and thus availability by the creatine kinase enzyme. β-guanidinopropionic acid (bGPA, simply GPA or N-(aminoiminomethyl)-beta-alanine), an amino acid with a similar molecular structure as creatine, is such a molecule. GPA reduces the flux through the CK reaction, by reducing cellular creatine uptake and will thus effectively have similar effect as the genetic ablation of the CK enzyme, which does - probably to your surprise - not just hamper the viability of respective mouse mutants, but will also (and here we are getting back to the effects of nicotinic acid) improved their muscular endurance and lead to a shift from type II to type I fiber predominance (Van Deursen 1993; Ventura-Clapier 2004; Vaarmann, 2008).

In short, when you use 5g of creatine as a means to "load" your PCr stores, the administration of GPA will have an "unloading" effect. This effect has in fact been studies in a number of previous studies. The effects and potential side effects of GPA are yet unclear and that despite the notwithstanding that it is freely available on the market and *surprise* you may well have been taking very small quantities of it in the past (maybe even still are), since NO Xplode 2.0 is by no means the only supplement that contains small (and obviously undisclosed) amounts of GPA in its kitchen sink ... ah, I mean "proprietary blend" (see "Ask Dr. Andro: Are There NO Changes in the New N.O.-Xplode 2.0 Advanced Strength Formula?", read full article). Reason enough for Inge Oudman, Joseph F. Clark and Lizzy M. Brewster from the Academic Medical Center in Amsterdam (Netherlands) and the University of Cincinnati to conduct a systematic review to assess the effect of this substance on the mammalian energy metabolism (Oudman. 2013).

So what did the scientists find? Is GPA the "next creatine" we've been waiting for?  ;-)

The primary outcome of the review was the effect of GPA on energy metabolism, function, and morphology of tissues "with high and fluctuating energy demands" (Oudman. 2013) - this includes the obvious,...

• skeletal muscle, where it reduces creatine, phosphocreatine, total creatine, and ATP by 66.1%, 79.7%, 86.7% , and 38.8%, blunted the total creatine kinase activity (-28.6%), but increased the intra-mitochondrial creatine recycling (CK activity) by 200%, reduced the activity of glycolytic enzymes (phosphorylase -38.8%, lactate dehydrogenase -16.2%), increased AMPK expression by 45% and AMPK mRNA by 20%, promoted GLUT-4 expression (+45% in slow-, +33% in fast twitch fibers) and subsequently doubled muscle glycogen content, while decreasing blood glucose (-5%) and insulin levels (-27% in non-diabetic animals), improved endurance during non-/light weight bearing exercises and hampered it during heavier exercise, doubled mitochondrial DNA (evidence for the shift towards an oxidative muscle type), and decreased total and relative muscle weight by 19% and 10% respectively;
• heart muscle, where similar decreases in creatine, phosphocreatine, total creatine, and ATP occurred and GPA decreased the survival rates after myocardial infarction by ~50%

but also the vascular musculature, where no significant effects were observed, in the central nervous system and the brain, where GPA reduced the creatine concentration (brain), doubled the adenylate kinase and succinate dehydrogenase activity (both are involved in energy reallocation), increased the risk of seizures, but showed potentially protective effects against neurodegenerative diseases.  Furthermore the scientists report that GPA reduced creatine uptake in the kidney, reduced the body temperature and increased the amount of BAT (+3.4%, in rodents!). And last, but certainly not least, GPA delayed the development of mammary gland tumors in a rodent model (cf. Chira. 1995; Metzner. 2009)

To summarize...

It looks like a marathon supplement, but it's not even sure that endurance athletes would benefit from taking GPA. In the off.season it could "intensify" the training, but before a race it appears to be rather counter-indicated (photo trainerjosh.com).

Overall the review confirms the notion that the administration of GPA leads to marked reductions in creatine, phosphocreatine, and ATP concentrations and reduces cytosolic, while increasing mitochondrial CK activity in skeletal muscle. These observations stand in line with a shift from a glycolitic to a mitochondrial oxidative metabolism that is facilitated / goes hand in hand with

• a shift from type II to type I fiber predominance,
• increased glucose tolerance, and
• reduced skeletal muscle and body weight

which do not incidentally remind us of the adaptive responses to endurance exercise. It goes without saying that mainstream science is psyched about the "reduced body weight with unchanged food intake" of which the Oudman et al. argue that it "may be related to the fiber type shift, as an association between type II fiber predominance and body weight was previously reported".

Other, per se unquestionably more favorable confounding factors are the increased cellular fatty acid transporter protein concentration, fatty acid oxidative capacity and the compensatory increase in AMPK expression that is actually a response to the perceived energy (ATP) deficiency that develops in response to the administration of GPA (click here to learn more about AMPK's role in fatty acid oxidation and glucose metabolism). So, as paradox as it may sound: Despite its negative effects on the use of glucose as a substrate GPA could actually improve, not deteriorate glucose metabolism via an AMPK mediated "metformin-esque" effect on GLUT-4 expression.

---

Way too many trainees tend to forget the true meaning of "supplement". Supplements are something that "supplement" something else. In the case of creatine supplementation the latter supplements your efforts in the gym and won't (and this has recently been confirmed) build muscle on its own.

So what's the verdict then? Now, all that does certainly sound pretty cool, well - at least for a cut - so would it be better to avoid creatine for leaner muscle gains and use GPA, whenever you are cutting? The first of these bottom-line questions is easy to answer: No! Studies have repeatedly shown that creatine supplementation does not only increase the mass gains, it also improves the ratio of lean to fat mass more than resistance training alone (as long as you the baseline diets are identical).

What about GPA as a diet tool, then? While it certainly would appear that taking (hitherto by the way unknown) amounts of GPA could help you lose weight, it is unlikely that this weight loss will make you look the way, you want to look. I mean if you have to lose weight at all costs, because your health depends on it, GPA could provide a viable AMPK promoter that may help you achieve just that.

Especially strength athletes, sprinters and the like, as well as anyone wanting to look / perform like one of these athletes should yet resort to the tried and proven dietary tweaks to get rid of the extra weight. And there is actually no reason not to continue taking a regular maintenance dose of 3g of creatine during the cut,also in view of the fact that the "beneficial" effects of GPA supplementation are actually brought about by blocking one out of two energy sources - much like keto dieting, by the way, but that's a topic for another blogpost ;-)

Related read: "Ask Dr. Andro: The Pharmacokinetics of Creatine"- Part I & Part II

References:

• Chwalbiñska-Moneta J. Effect of creatine supplementation on aerobic performance and anaerobic capacity in elite rowers in the course of endurance training. Int J Sport Nutr Exerc Metab. 2003 Jun;13(2):173-83.
• Metzner L, Dorn M, Markwardt F, Brandsch M. The orally active antihyperglycemic drug beta-guanidinopropionic acid is transported by the human proton-coupled amino acid transporter hPAT1. Mol Pharm. 2009; 6: 1006– 1011.
• Ohira Y, Inoue N. Effects of creatine and beta-guanidinopropionic acid on the growth of Ehrlich ascites tumor cells: i.p. injection and culture study. Biochim Biophys Acta. 1995; 1243:367–372.
• Oudman I, Clark JF, Brewster LM. The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review. PLoS One. 2013;8(1):e52879.
• Vaarmann A, Fortin D, Veksler V, Momken I, Ventura-Clapier R. Mitochondrial biogenesis in fast skeletal muscle of CK deficient mice. Biochim Biophys Acta. 2008; 1777: 39–47.
• Vanakoski J, Kosunen V, Meririnne E, Seppälä T. Creatine and caffeine in anaerobic and aerobic exercise: effects on physical performance and pharmacokinetic considerations. Int J Clin Pharmacol Ther. 1998 May;36(5):258-62.
• Van Deursen J, Heerschap A, Oerlemans F, Ruitenbeek W, Jap P. Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell. 1993; 74: 621–631
• Ventura-Clapier R, Kaasik A, Veksler V. Structural and functional adaptations of striated muscles to CK deficiency. Mol Cell Biochem 2004; 256–257: 29–41.