Creatine Uptake, Bioavailability, and Efficacy - We've Gotten it all Wrong and Low Serum Creatine Levels are Better!?

Creatine Uptake, Bioavailability, and Efficacy - We've Gotten it all Wrong and Low Serum Creatine Levels are Better!?

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If you put some faith into the marketing campaigns of supp producers, there's a creatine for everyone: one to get lean, one to get strong and one to get big and buffed... bullocks!

It has been a while since I've discussed the bioavailability of different forms of creatine. On various supplement sites, the notion that there was one form of creatine that was significantly more bioavailable and would thus allow you to 'load' muscle phosphocreatine (PCr) faster and more efficiently is obviously still a matter of constant debate... a debate of which the latest study by Ralf Jäger et al. (2016) indicates that it may argue based on a fundamentally flawed premise, i.e. that higher serum levels of creatine after the ingestion of a given product would signify an increased efficacy in terms of performance / strength / size gains.

How come? Well, the previously mentioned, as of yet unpublished data from a study by Ralf Jäger, Martin Purpura, and Roger C Harris did not just confirm the results of previous studies, which indicate that glucose (75g) and alpha lipoic acid (ALA | 200mg) will increase the bioavailability of creatine, i.e. "the proportion of a drug or other substance [in this case creatine] that enters the circulation when introduced into the body" (Merriam-Webster.com), it also indicates that the practically relevant predictor of creatine's efficacy is - assuming equal dosing and complete absorption - not a high, but rather a low level of creatine in the blood.

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What? Let me explain: Initially, it may be worth pointing out that we are talking about a small scale study the results of which have not yet been published in the peer-reviewed journal. In that study, Jäger et al. aimed to compare the effects of ingesting tricreatine citrate (5g, TCrC),

• in combination with 75g of glucose and 200mg of alpha-lipoic acid, or
• without the former bioavailability enhancers.

on only six subjects. These three men and three women (35.5+/-14.5 yrs, 172.5+/-12.2 cm, 75.3+/-9.0 kg), who were all healthy, normal-weight and non-vegetarian and thus not, with creatine being a deficiency nutrient in vegetarians, extraordinarily susceptible to creatine supplementation (Burke. 2003), participated in two testing sessions during which they received the previously explained two treatments (the powdered supplements were simply dissolved in 450 ml of water).

Adding carbohydrates or cinnamon to creatine may well increase its uptake to the muscle. What it does not do, however, is to enhance creatine's efficacy - at least not in a 2015 3-week creatine loading study Islam et al. conducted in 25 recreational gymrats.

What's the increased absorption worth? If we rely on a a recent study by Islam, et al. (2015) the answer is (unfortunately) nothing. In their 2015 study, the scientists from the Wilfrid Laurier University and the University of Lethbridge in Canada found no (=zero) significant differences in anaerobic power, strength, and endurance when creatine was administered solo, with the same 70 g carbohydrate (CHO) that were used in Jäger et al. (2016), or 500 mg cinnamon extract (CIN), of which the authors believed that its proven ability to improve insulin sensitivity and up-regulate glucose transport in skeletal muscle would likewise enhance the uptake of creatine in the muscle and thus make it more effective.

With their cross-over after the initial test and a 7 day break between the tests, the scientists would have been able to compare the effect of adding glucose and alpha lipoic acid to the tricreatine citrate (Creapure™ Citrate, AlzChem, Trostberg, Germany | 65% w/w creatine) on an individual level. Corresponding data, however, is not (yet?) available. Instead, we get the likewise interesting statistical averages (see Figure 1):

Figure 1: Mean plasma creatine concentration over 8 hours following ingestion of 5g tricreatine citrate (TCrC) and 5g tricreatine citrate + 75g glucose + 200mg alpha-lipoic acid (TCrC+Glu+ALA | Jäger. 2016).

And these data present a quite intriguing result. More specifically, they indicate that the increase in peak concentration and the area under the curve (indicative of the total amount of creatine that appeared in the blood of the subjects) were significantly lower in the TCrC+Glu+ALA group in comparison to TCrC (75.3%, p<0.05, and 82.2% respectively).

Less creatine in the blood with sugar + ALA? That's bad, right? No that's good!

Just as the likewise lower 0.5 and 1h plasma concentrations of creatine, in the TCrC+Glu+ALA group (in comparison to TCrC), these reductions do not indicate a reduced efficacy of the supplement. On the contrary! The significantly elevated mean 8h urinary creatine elimination in the control group (TCrC | 26.5 ± 13.9% of the dose administered  vs. 17.2 ± 13.0% for TCrC+Glu+Ala) rather indicates that the addition of glucose and ALA "enhanced rate of creatine uptake into the muscle" - as previous studies indicate probably due to the presence of raised insulin (by glucose) and / or an increased insulin sensitivity (by ALA / Koszalka. 1972; Steenge. 1998; Pittas. 2010).

Figure 2: The study on creatine + glucose and creatine + cinammon by Islam et al. (red box) is not the only one that shows that the increased deposition of creatine in the muscle doesn't give you athletic advantages. The exact same results have been observed in an 8-week study comparing 70 g of a dextrose placebo (PL), 5 g creatine/70 g of dextrose (CRD) or 3.5 g creatine/900 mg fenugreek extract (CRF) by Taylor et al. (2011)

Why's this study relevant? Well, the answer should be obvious. The few allegedly 'advanced creatine products' on the market that actually have scientific back-up of their efficacy often refer to studies showing increases in plasma creatine of which the study at hand shows that they are no valid predictor of the actual efficacy of the supplement. The latter obviously depends on muscle creatine uptake, not serum peak levels or AUC. Don't be a fool, though: This does not mean that lower serum levels after ingestion were automatically better. After all, those lower levels of creatine in the blood may well be a mere result of an impaired / incomplete absorption in the gut.

Confusing? Well, let's summarize: By measuring the creatine level in the blood and the excretion of creatine in urine, Jäger et al. were able to refute the (ostensibly) logical assumption that higher serum creatine levels would indicate an improved efficacy. What they did not prove conclusively, however, is that the creatine levels in the muscle were in fact significantly higher (no biopsies) and, most importantly, that this makes a performance difference. The latter has after all been refuted in previous studies, such as Islam et al. (2015 | see red box and Figure 2). The hunt for the "best form" of creatine will thus probably go on, albeit with different experimental means, i.e. either the measurement of serum and urinary creatine as it was done in the study at hand or (even better) the direct assessment of muscle creatine stores and the actual performance benefits | Comment!

References:

• Burke, Darren G., et al. "Effect of creatine and weight training on muscle creatine and performance in vegetarians." Medicine and science in sports and exercise 35.11 (2003): 1946-1955.
• Jäger, Ralf, Martin Purpura and Roger C Harris. "Reduction of Plasma Creatine Concentrations as an Indicator of Improved Bioavailability." Upublished data from privatt conversation (2016).
• Koszalka, Thomas R., and Carole L. Andrew. "Effect of insulin on the uptake of creatine-1-14C by skeletal muscle in normal and X-irradiated rats." Experimental Biology and Medicine 139.4 (1972): 1265-1271.
• Pittas, G., et al. "Optimization of insulin-mediated creatine retention during creatine feeding in humans." Journal of sports sciences 28.1 (2010): 67-74.
• Steenge, G. R., et al. "Stimulatory effect of insulin on creatine accumulation in human skeletal muscle." American Journal of Physiology-Endocrinology And Metabolism 275.6 (1998): E974-E979.
• Taylor, Lem, et al. "Effects of combined creatine plus fenugreek extract vs. creatine plus carbohydrate supplementation on resistance training adaptations." Journal of sports science & medicine 10.2 (2011): 254.

Want to Home-Brew Your Own 15x More Bioavailable Super-Curcumin? Buy Buttermilk and a Yogurt Starter Culture

Want to Home-Brew Your Own 15x More Bioavailable Super-Curcumin? Buy Buttermilk and a Yogurt Starter Culture

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No one says you cannot add other ingredients to the yogurt to make it more tasty if you add the curcumin before fermenting the buttermilk.

If you're a regular at the SuppVersity you will know that curcuminoids, the polyphenols found in turmeric roots (Curcuma longa), have health effects that are similar, in some cases even superior to several anti-inflammatory, anti-diabetic and lipid-lowering drugs. Yes, their consumption has even been linked to significant reductions in cancer risk. Unfortunately, there's a problem with these powerful polyphenols: they are hydrophopbic (Tønnesen. 2002) and prone to degradation in an aqueous environment at neutral and alkaline pH (Tønnesen. 1985; Wang. 1997) - two properties of which Gupta and others (2013) believe that they are responsible their poor oral bioavailability.

Unlike other supps and practices curcumin has not been shown to interfere with hormesis

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Low bioavailability or not, Shishan Fu and rightly highlight in the introduction of their latest paper, even the hardly absorbed "regular" curcuminoids have been reported to offer many health-promoting properties (Gupta and others 2013), it is thus only logical that there's an "interest in the development of functional foods containing these compounds is increasing" (Fu. 2016).

Figure 1: Even dispersing them in buttermilk will increase the bioavailability by decreasing the breakdown of curcuminoids during digestion - that's at least what a 2014 study by Fu et al. shows. 

Hitherto scientists have (more or less successfully) tried to increase the solubility and stability of curcuminoids by dispersing them in matrices such as lipid-based emulsions (Ahmed. 2012; Yu and Huang. 2012), modified starch (Yu and Huang 2010), hydroxypropyl methyl cellulose (Chuah. 2014), milk proteins (Yazdi and Corredig. 2012), and buttermilk (Fu. 2014). As Fu et al. point out, ...

"[...t]he bioavailability may also be increased when formulated in appropriate delivery systems. For example, lecithin–piperine formulations containing curcuminoids and curcuminoids encapsulated in cellulose have been reported to have enhanced bioavailability after oral administration in humans (Antony and others 2008; Vitaglione and others 2012)" (Fu. 2014).

Based on their own previous study with regular buttermilk and evidence that yogurt can significantly increase the stability and bioavailability of bioactives, like green tea polyphenols (Lamothe and others 2014), Fu et al. speculated that dispersing curcuminoids in buttermilk prior to yogurt manufacture would exert even more powerful effects than simply mixing them with buttermilk (see Figure 1). To test this hypothesis, the scientists did something anyone of you can do at home (see Figure 2 for information on how the control samples were prepared, too):

Figure 2: Preparation of yogurts (Fu. 2016).

"A buttermilk dispersion (14% total solids, w/w) was prepared by reconstituting 142.3 g of buttermilk powder in MilliQ-water which was made up to 1000 g. The powder was dispersed in the water at 45 °C with stirring using an overhead stirrer (Heidolph RZR 2051 control, Germany) at 1000 rpm for 30 min. The dispersion was then stored at 4 °C overnight for more complete hydration. The chosen fortification level of curcuminoids in yogurt was 300 mg/ 100 g yogurt (0.3% w/w)

An ABT-5 culture was prepared by mixing 0.2 g of culture granules in 10 mL of buttermilk dispersion (14% total solids, w/w) and stirring for 15 min in an ice bath. This culture solution was prepared freshly prior to fermentation. The ABT-5 culture was added at a level of 0.2 g/L of yogurt buttermilk. The buttermilk was subsampled (50 mL) into separate plastic containers and incubated at 43 °C until pH reached 4.6. These set yogurts were put into the ice water bath for 30 min, stirred at 200 rpm for 20 s using a mixer (Heidolph RZR 2050, Germany) and then stirred manually (approximately 20 times) to obtain a uniform product. The stirred yogurts were stored in a cool room (4 °C) overnight. All analysis was completed within 2 d of yogurt manufacture. The total solids of the yogurts were estimated using a moisture analyser (Sartorius AG, Germany)." (Fu. 2016).

To be able to tightly control the experiment, the curcumin enhanced yogurt and the other samples were exposed to in vitro digestion. During this procedure, the sample (5 g) was mixed with 15 mL of simulated gastric fluid (SGF) containing 2 g NaCl and 7 mL 37% w/v HCl per liter (pH 1.23) and 3.2 mg/mL pepsin, and incubated in a water bath with 100 rpm at 37 °C for 2 h (United States Pharmacopeia Convention 2009).

"After exposure to SGF, the mixture was adjusted to pH 6.5 using 1 M NaOH and mixed with 9.6 mL of simulated intestinal fluid (SIF) containing 3 mL of 2 M NaCl, 0.3 mL of 0.075 M CaCl2, and 6.3 mL of 36.5 mg/mL bile extract in 5 mM phosphate buffer. The pH was adjusted to 6.8 and then 5.4 mL of 10 mg/mL pancreatin in phosphate buffered saline was added. Samples were incubated at 37 °C, 100 rpm for 3 h and then placed in an ice bath to arrest the enzyme activity. At the end of the in vitro digestion period curcuminoids were extracted from the whole digested mixture with acetone and quantified using HPLC-DAD" (Fu. 2016). 

The in-vitro digestion, which is described in a previous paper by Fu et al. (2015), provided the scientists with an estimate of the amount of undegraded curcuminoids - it is yet not a 100% reliable method to determine the real world biological effects in humans, which would have to be tested in future studies. In view of the fact that the scientists calculations show that the resistance of the curcuminoids to degradation after sequential exposure to SGF and SIF improved more than just statistically significantly (see Figure 3), it is logical to assume that benefits would be observed in vivo, too.

Figure 3: Bioaccessibility of curcuminoids after sequential exposure of samples to SGF and SIF (Fu. 2016).

The difference pre-processing, i.e. the prior dissolution in ethanol (which wouldn't make you drunk, anyway, because the total ethanol content of the yogurt would be marginal), the dissolution of curcuminoids in buttermilk and its fermentation to "curcumin enhanced" buttermilk yogurt with a standard ATB yogurt starter culture, made in terms of the bioavailability is after all huge.

In fact, the bioavailability of the curcuminoids increased to an extent that easily surpasses the hyped BCM-95®, a combination of curcumin and bioperin, which has been shown to exhibit a 6.93-fold higher bioavailability. In all fairness, we shouldn't forget, though, that, unlike the yogurt trick described here, Biocurcumax™ has already been studies in humans (Antony. 2008).

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The total bioavailability is still low, but... As, Fu et al. point out in the conclusion of their soon-to-be-published paper, "[t]he most important and practical finding from the bioaccessibility data is that the incorporation of powdered curcuminoids into buttermilk prior to yogurt manufacture results in a 15-fold increase in bioaccessibility of curcuminoids compared to that of neat curcuminoids dispersed in aqueous buffer" (Fu. 2016).

The scientists are yet also right to point out that even with the enhanced bioaccessibility of curcuminoids the total bioavailability was still low (approximately 6%) when they were delivered in yogurt.

In view of the fact that the polyphenols which are transferred into the colon are degraded by gut microflora and the degradation products contribute to the bioactivity of these compounds in the body, the real-world relevance of this astonishing increase in bioavailability will have to be tested in in vivo, before we can have a final say on the practical significance of these findings | Comment!

References:

• Ahmed, Kashif, et al. "Nanoemulsion-and emulsion-based delivery systems for curcumin: encapsulation and release properties." Food Chemistry 132.2 (2012): 799-807.
• Antony, B., et al. "A pilot cross-over study to evaluate human oral bioavailability of BCM-95® CG (Biocurcumax™), a novel bioenhanced preparation of curcumin." Indian journal of pharmaceutical sciences 70.4 (2008): 445.
• Chuah, Ai Mey, et al. "Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin." Food chemistry 156 (2014): 227-233.
• Fu, Shishan, et al. "Bioaccessibility of curcuminoids in buttermilk in simulated gastrointestinal digestion models." Food chemistry 179 (2015): 52-59.
• Fu, Shishan, e al. "Enhanced Bioaccessibility of Curcuminoids in Buttermilk Yogurt in Comparison to Curcuminoids in Aqueous Dispersions." Journal of Food Science (2016): Ahead of print. doi: 10.1111/1750-3841.13235
• Yazdi, S. Rahimi, and M. Corredig. "Heating of milk alters the binding of curcumin to casein micelles. A fluorescence spectroscopy study." Food Chemistry 132.3 (2012): 1143-1149.
• Yu, Hailong, and Qingrong Huang. "Enhanced in vitro anti-cancer activity of curcumin encapsulated in hydrophobically modified starch." Food Chemistry 119.2 (2010): 669-674.
• Yu, Hailong, and Qingrong Huang. "Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions." Journal of agricultural and food chemistry 60.21 (2012): 5373-5379.