Written by justis berg
03 May 2010
Shred of Evidence

By Anthony L. Almada, MSc, FISSN

Creatine Commandments II: Myostatin and Insulin Revelations

When the little cloud opened up and presented the first two commandments to MD readers ("Shred of Evidence," September 2009), groans and grumblings were heard— along with several people telling me at the 2009 Mr. Olympia, "I didn't know that about creatine!"

In this new 'visit' from the heavens, we hear from one of the true creatine gods (out of the U.K.) and a previously-unknown group of researchers from our good friends at... you guessed it, Tehran University in Iran.

3. Creatine monohydrate uptake is augmented by sufficiently high increases in blood insulin, which can be increased through various nutritional means.

The first creatine commandment is that creatine monohydrate provides a source of creatine that easily survives transit through the 'acid war zone' of the stomach, and is very well absorbed— in humans. Abundant evidence supports this, including the first human study back in 19921, and zero published human studies refute this (ye of little faith and weak spines— just ask for proof to the contrary, in the form of human studies published in a scientific journal...good luck!).

Now let's think about creatine after it has entered the blood: as with almost all performance- or metabolism-modifying agents, the blood is simply a highway to the strategic destination in the form of certain target tissue(s): the brain, the liver, skeletal muscle, the pancreas, etc. It typically needs to enter this target and then it starts to exert its cellular effects— that translate into whole-body effects that can be seen, felt or measured.

Some dietary supplements, like creatine and carbohydrate, exhibit contrary behavior when present in the blood around the same time as insulin. For example, a 5-gram dose of creatine monohydrate can raise blood creatine concentrations 15 times higher than before the creatine dose, but... if something that can raise blood insulin to a high enough degree is consumed with or around the same time as the creatine monohydrate, the apparent rise in creatine is cut down,2 just like the apparent glycemic rise is cut down if the food or supplement causes a large or faster rise in insulin3 ("Shred of Evidence," February 2010).

Why is insulin's rise cut down? This apparent 'lower absorption' (because less creatine is measured in the blood) is actually indicative of creatine entering the blood and then being quickly 'siphoned' off by insulin-driven activation of creatine transporter proteins that are 'imbedded' in muscle cells. It's just like the draining effect of insulin, siphoning off glucose out of the blood and into muscle cells, effectively making a high-glycemic carb a lower-glycemic carb.3

But let's get back to target tissues— like muscle. When we first advocated (during 1993-1994 at EAS) combining creatine monohydrate with dextrose, we didn't have any evidence to support this sugar-loading practice— except the assumption that a spike in insulin would increase creatine transport. Since then, several studies have been done, some involving taking the creatine at a time separate from the sugars,4 or taking sugars + protein.5

One of the downsides of this approach is, as this commandment states, that insulin needs to be raised to a 'sufficiently high' value to promote greater muscle/whole-body creatine retention. Taking in about 100 grams of sugars to boost creatine uptake is like drinking 10 cans of cheap, light beer to get drunk— the calorie load is substantial.

The same lab that did much of the pioneering work in creatine, including the first creatine + insulin/carbs studies— Dr. Paul Greenhaff's laboratory at the University of Nottingham in England— has revised the commandment.6 In a recent study, they compared 5 grams of creatine monohydrate (taken twice over four hours) combined with one of three 'mixes': 1) water, 2) 95 grams of dextrose, or 3) 14 grams whey protein hydrolysate, 7 grams leucine, 7 grams phenylalanine, and 57 grams dextrose. They found whole-body creatine uptake/retention (measured by how much creatine was excreted in the urine— the less excreted, the more retained) was significantly greater with the dextrose, or dextrose + whey protein isolate (WPI) and insulin-releasing amino acids. No difference was seen between the two insulin-booster mixes.

This study, funded by Iovate/MuscleTech, offers a lower-carb approach to optimizing creatine retention, from the same lab that 'invented' the creatine-insulin connection. How this brew would taste is a different story.

2. Creatine increases muscle mass via mechanisms that remain a mystery.

Back in creatine's infant years— the early-to-mid-'90s— we coined the phrase 'cell-volumizing,' thinking (hoping) that creatine exerted its gains in mass by increasing the amount of fluid volume present inside muscle cells, and through the anabolic metabolic cascade that follows. This has never been proven to operate in humans. In his "Supplement Performance" column in January 2010 MD, Robbie Durand told us about a recent study showing that creatine monohydrate supplementation increases the dihydrotestosterone:testosterone ratio in male collegiate rubgy players.7 However, the rugby players in this study did NOT show any improvement in body composition to a dextrose placebo.

The newest spin as to how creatine monohydrate may increase muscle mass and performance comes from a study done by Iranian researchers, and it comes via the messenger called myostatin. Untrained collegiate male subjects were put through an eight-week resistance-training program, with half the subjects taking creatine monohydrate capsules (bodyweight-specific loading dose in three divided doses for one week, single maintenance dose for seven weeks), or cellulose placebo capsules— the same amounts as the creatine monohydrate group.8 Body composition, muscular strength, and blood concentrations of myostatin, and a myostatin-binding protein called... hold your breath... GASP-1, were measured throughout the study.

What did the researchers find? The creatine monohydrate group showed greater gains in lean mass, and bench and leg press after eight weeks (yawn). Notably, both training groups showed a significant drop in blood myostatin, as was seen in a previous study9 but not another.10 What made this study unique was the 'breathtaking' finding that GASP-1, one of the 'inhibitors' of myostatin, was increased by resistance training (which may explain the reduction of blood myostatin). However, creatine monohydrate supplementation did not lead to a greater increase in GASP-1.

We mortals may never know how creatine exerts its anabolic effects. We now know that creatine monohydrate can augment myostatin reductions greater than training alone, and (most importantly), the myostatin-blunting via creatine monohydrate is associated with greater strength and lean mass gains.


1. Harris RC, et al. Clin Sci, 1992;83:367-74.

2. Steenge G, et al. Am J Physiol Endocrinol Metab, 1998:275: E974-E979.

3. Schenk S, et al. Am J Clin Nutr, 2003;78(suppl):742-8.

4. Green AL, et al. Am J Physiol Endocrinol Metab, 1996;271:E821-E826.

5. Steenge G, et al. J Appl Physiol, 2000;89:1165-71.

6. Pittas G, et al. J Sports Sci, 2010;28:67-74.

7. van der Merwe J, et al. Clin J Sport Med, 2009;19:399-404.

8. Saremi A, et al. Mol Cell Endocrinol, 2010; doi:10.1016/j.mce.2009.12.019

9. Walker KS, et al. Med Sci Sports Exerc, 2004;36:787-93.

10. Willoughby DS. Med Sci Sports Exerc, 2004;36:574-82.

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