by Alfredo Franco, PhD
Creatine is, by no means, new to this world. Creatine is, and always has been, a natural constituent of skeletal muscle. Humankind simply needed to be made aware of its existence. Amazingly, creatine was first identified nearly two centuries ago! In the early 1800s, the French scientist and philosopher, Michel-Eugène Chevreul, isolated a novel agent from skeletal muscle that he later named creatine for kreas, the Greek word for flesh (1).
A few years later (1847), a German scientist named Justus von Liebig observed that maintaining foxes in captivity decreased their muscular creatine content (2). Postulating that physical activity increases creatine uptake by skeletal muscle, Liebig advanced the hypothesis that muscles utilize certain nitrogen containing molecules for energy. These nitrogenous molecules, otherwise known as amino acids, include creatine. Intriguingly, as an extension of his findings, Liebig later lent his name to a commercial extract of meat, which he asserted would help the body perform extra “work”. In fact, “Liebig’s Fleisch Extrakt” could quite reasonably be considered the original creatine supplement (complete with marketing plan). Near the turn of the last century the first studies examining the effects of creatine feeding were conducted where it was noticed that not all the creatine fed to animals could be recovered in the urine. Soon afterwards, Otto Folin and W. Dennis (1912-1914) of Harvard University (Boston) unequivocally corroborated by that the body’s musculature retains the greater part of any ingested creatine.
Therefore, nearly one century ago scientists had already come full circle, from discovering that skeletal muscle is the richest natural source of creatine to the largest sink for dietary creatine in the body. Nevertheless, up to quite recently, the manner in which to best promote creatine absorption by skeletal muscle remained largely elusive. In this respect, a huge leap forward was made with the finding that insulin assists in the absorption of creatine into skeletal muscle. And, although this effect was previously hinted at in animal studies, the studies that first clearly showed this effect in humans were conducted only a few years ago (3,4). These human studies used glucose to stimulate the production of insulin, the same agent used by the body for this same purpose.
Following a meal our blood glucose levels rise, which then serves as the signal for the release of insulin from the pancreas. Insulin, in turn, enables the cells of our body to take up nutrients, principally glucose, but also amino acids, from the blood stream. Creatine, due to its structural likeness to amino acids, is also transported into the cell with the assistance of insulin, although via a different transport pathway. In this respect, insulin sets the stage for muscle growth (aka, anabolism) by making available to the cell the basic substrates for the production of new muscle tissues.
The problem with the original studies examining insulin-mediated creatine uptake in humans, however, was that the amounts of glucose required to evoke a strong enough release of insulin were exorbitant; nearly 20 grams of glucose for each gram of creatine consumed and close to the limit of palatability for most individuals. Furthermore, this amount of glucose, if consumed on a regular basis, could lead to a state of insulin-resistance, which is the path to the development of type II diabetes. In other words, cells become immune to the presence of insulin if constantly bombarded by it, which, in turn, diminishes the uptake of essential nutrients into muscle cells and increases the need for insulin to stimulate muscle growth. Furthermore, since fats cells are the last to become resistant to the effects of insulin, the initial stages of insulin-resistance causes our fat reserves to swell and our muscle mass to shrivel up. Therefore, although these results were promising, they were far from being a complete solution.
Since then, there has been a search for agents that might effectively release insulin into the blood stream (for the purpose of creatine adsorption) without adversely influencing insulin-sensitivity. Many creatine manufacturers have consequently taken to adding a variety of insulin-agonists to their products in hopes of getting around the insulin-dilemma. These “insulinotropic” strategies are aimed at either enhancing the release of insulin from the pancreas or augmenting the effects of upon the cell in order to increase transport rates of creatine into skeletal muscle. The agents often used for this purpose include chromium picolinate, alpha-lipoic acid, 4-hydroxyisoleucine, and the amino acids, taurine, L-arginine, NO-releasers, and L-carnitine. These days it is quite common to find one, or more, of these agents in many creatine products. Unfortunately, with the exception of alpha-lipoic acid (5), none of these agents have been specifically shown in scientific studies to potentiate the uptake of creatine into the cell. This in time may come, but for the moment, it’s still too early to say whether these other agents actually promote creatine absorption by muscle cells.
There’s a safer, and much more reliable, method of promoting insulin release that has been overlooked by many creatine manufacturers. Ignored, in fact, simply because it isn’t sexy enough to appear innovative and, consequently, will not serve to jack up the price of the product; the agenda of most creatine manufacturers. By now, the ability of glucose to release insulin is without dispute. Ten years ago, however, a study showed that protein greatly potentiates the ability of glucose to release insulin into the blood stream from the pancreas (6). The effect of protein was so powerful that half the amount of carbohydrates could be used to elicit the same amount of insulin release.
What remained to be shown was whether the combination of carbohydrates and protein is equally as effective at promoting creatine absorption by skeletal muscle. This awaited study finally appeared in 2000 and showed that protein in combination with simple carbohydrates augments creatine absorption by skeletal muscle to a similar extent as high doses of carbohydrates (7). In this study experimental subjects were given one of four different supplement combinations 30 minutes after ingesting creatine, 5 grams of glucose (placebo), 50 grams of protein and 47 grams of glucose (PRO-CHO), 96 grams of glucose (Hi-CHO), or 50 grams of glucose (Lo-CHO). The results were clear, PRO-CHO and Hi-CHO were equally effective at promoting creatine absorption, which were both greater (~10-25%) than either Lo-CHO and placebo. Again, adding protein reduced the glucose requirement by half!
Another advantage of adding glucose to your creatine is that it aids in the replenishment of your glycogen reserves following exercise. This effect arises from the ability of insulin to increase the number of glucose transporters (GLUT 4) expressed on the cell surface. GLUT 4 is the principal protein complex responsible for transporting glucose into the cell once stimulated by insulin. And, since exercise makes the cells of our body more sensitive to the effects of insulin, exercise likewise increases the expression of GLUT 4. On the other hand, inactivity, either by choice or because of injury, reduces GLUT 4 expression.
Along these lines, a recent study has shown that creatine protects against the loss of GLUT 4 during limb immobilization and, furthermore, accentuates the increased expression of GLUT 4 during subsequent rehabilitation (8). Not surprisingly, the creatine and glucose treated subjects exhibited larger muscle glycogen (and creatine) reserves during rehabilitation. Finally, a new study just appeared indicating that protein exerts a similar effect on GLUT 4 expression, but without adversely affecting insulin-sensitivity (9). Specifically, this study compared the effects of creatine supplementation with glucose or glucose plus protein during the rehabilitation of a previously immobilized limb. The authors of this study found that retraining (6 weeks) a previously immobilized limb (2 weeks placed in a cast) in conjunction with a post-exercise creatine, protein and glucose meal increased GLUT 4 expression and muscle glycogen content to the same extent as a creatine and glucose meal. Most importantly, since the protein meal contained less than one third the amount of glucose (20 grams versus 70 grams!), insulin sensitivity was improved as a result. Furthermore, the effect on glycogen storage was specific for the exercised limb. That is, the un-exercised limb exhibited no change in GLUT 4 expression or muscle glycogen content. This result clearly indicates that simply upplementing with creatine, irrespective of the manner in which it is done, in the absence of exercise is a fruitless endeavor.
The solution seems clear. Adding protein to your creatine and carbohydrate mix will promote muscle creatine uptake (and glycogen synthesis) WITHOUT adversely affecting the sensitivity of your cells to insulin.
Author’s Note: Due to space constraints, other very important anabolic benefits of combining protein and creatine were not covered in this article. These other anabolic attributes, and how to best make use of them, are discussed in my creatine guide. Click here for more information about the guide.
1. Chevreul, X. (1835) Sur la composition chimique du bouillon de viandes. J. Pharm. Sci. Accessoires Volume 21: pages 231-242.
2. Balsom, P. D., Soderlund, K. and Ekblom, B. (1994) Creatine in humans with special reference to creatine supplementation. Sports Medicine Volume 18: pages 268-280.
3. Green, A. L., Simpson, E. J., Littlewood, J. J., MacDonald, I. A., and Greenhaff, P. L. (1996). Carbohydrate ingestion augments creatine retention during creatine feedings in humans. Acta Physiol Scand Volume 158: pages 195-202.
4. Steenge, G. R., Lambourne, J., Casey, A., MacDonald, I. A., and Greenhaff, P. L. (1998). Stimulatory effect of insulin on creatine accumulation in human skeletal muscle. American Journal of Physiology Volume 275: pages E-974-E979.
5. Burke, D. G. Chilibeck P. D., Parise G., Tarnopolsky M. A., and Candow D. G., (2003). Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine and phosphagen concentration. International Journal of Sports Nutrition and Exercise Metabolism Volume 13(3): pages 294-302.
6. Chandler, R. M., Byrne, H. K., Patterson, J. G., and Ivy, J. L. (1994). Dietary supplements affect the anabolic hormones after weight-training exercise. Journal of Applied Physiology Volume 76(2): pages 839-845.
7. Steenge, G. R., Simpson, J., and Greenhaff, P. L. (2000). Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans. Journal of Applied Physiology Volume 89: pages 1165-1171.
8. Op’t Eijnde, B., Urso, B., Richter, E. A., Greenhaff, P. L., and Hespel, P. (2001). Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes Volume 50: pages 18-23.
9. Derave, W. Op’t Eijnde, B., Verbessem, P., Ramaekers, M., Van Leemputte, M. Richter, E. A., and Hespel, P. (2003). Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans. Journal of Applied Physiology Volume 94: pages 1910–1916.
This article was written by Dr. Alfredo Franco, research scientist, author, and owner of the Creatine Information Center and NSN Publishing.
Dr. Franco has had over 20 years of in depth research experience in major laboratories world-wide. His principal scientific interest is the understanding of the cellular mechanisms leading to muscle cell death.
Dr. Franco is also the author of Creatine: A practical guide. Creatine: A practical guide clearly teaches you how to best combine exercise, nutrition, and intelligent creatine use for optimal muscle growth, improved athletic performance, and overall good health. Find out more about this must-read book.
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