Quick Hit Summary
The positive effects of creatine on lifting, sprinting and other high intensity anaerobic activities are widely recognized. However, what is less known is the beneficial role creatine supplementation may have on overall health. As discussed in part I of our “Creatine – Beyond Brawn” series, supplementing type II diabetics with 5g/day for 12 weeks has been shown to lower HbA1C, a marker for long term blood sugar measurement, by 1.1%. This drop in HbA1C is similar or greater than that commonly seen with metformin, the most common type II diabetic drug on the market today. Furthermore, when taken over this same time period, it does not seem to exert any deleterious effects on kidney health in type II diabetics. With regards to healthy individuals, creatine doesn't appear to have a large effect on blood glucose management. However, it does positively impact glycogen levels. Creatine positively impacts blood glucose management/glycogen storage capabilities by increasing the number of glucose transporters (GLUT-4) on the surface of muscle cells.
About the “Creatine – Beyond Brawn” Series
The ergogenic benefits that creatine has on muscular power and performance is widely known. However, what is less known is the “other” beneficial roles that creatine supplementation may have on health and in clinical settings. These “other” benefits will be the primary focus of our Creatine – Beyond Brawn series.
Prelude: Creatine – A Historical Look
Creatine – Beyond Brawn Part I: Diabetes and Glycemic Control
Creatine – Beyond Brawn Part II: Nervous System Health
Creatine – More Than Simply a Muscle Builder
Figure 1. Creatine – A supplement which actually lived up to the hype. Image Source14
If I asked 100 different individuals to give me their top 5 ergogenic supplements for athletes/trainees participating in high intensity anaerobic activities, I'd probably get 100 different lists. However, if I asked 100 different individuals what the TOP ergogenic supplement on the market was for this same group of athletes/trainees, I'm quite confident that creatine would be the clear cut winner. It is one of the few supplements that has actually lived up to the hype. As stated in the International Society of Sports Nutrition's (ISSN) Position Statement on Creatine:
"Creatine monohydrate is the most effective ergogenic nutritional supplement currently available to athletes in terms of increasing high-intensity exercise capacity and lean body mass during training."1
Although the ergogenic role that creatine has on anaerobic activities is common knowledge amongst most athletes/trainees, what is less known is the benefits that creatine has on overall health. In this multipart "Creatine – Beyond Brawn" series, we're going to examine some of these "other" benefits; starting off with its role in diabetes and glycemic control.
Move Over Metformin; A New Sheriff, Dr. Creatine, is in Town!
The idea that creatine may be an effective supplement for blood sugar management stems from research showing that the addition of creatine to carbohydrate supplements, in conjunction with exercise, improved muscle glycogen stores to a greater extent than carbohydrates alone.23 Even in the absence of exercise or additional carbohydrates supplements, creatine alone has been shown to increase muscle glycogen content.4 Additionally, research completed in animal models have shown creatine to have a beneficial effect on blood glucose management.5
Exercise Protocol for Gualano et al Study: 5 min treadmill warmup, 25 min resistance training (4×8-12 reps; bench press, leg press, lat pulldown, leg extension, seated row) 30 minute treadmill aerobic training (70% VO2max) followed by 5 minutes of stretching.
With this as a backdrop, Bruno Gualano and his fellow researchers at the University of Sao Paulo, Brazil, sought to find if creatine would benefit those with type 2 diabetes.6 To test this, the team had 25 diabetic individuals complete a 12 week exercise program (see side box for exercise protocol). In conjunction with the exercise program, half of them received 5 grams of creatine/day whereas the other half received a placebo. [It should be noted that all participants were also on metformin to control symptoms]. Before and after the 12 week training plan, the research team assessed acute blood sugar control using a 500 kcal meal tolerance test (60%CHO, 20% Fat, 20% PRO). Additionally they examined long term blood glucose management, via glycosylated hemoglobin (HbA1C).
Figure 2. HbA1C levels before and after 12 weeks of creatine supplementation. Below the orange dotted line represents the "goal" range for diabetics (HbA1C < 6.5-7%). Data adapted from Gualano et al.6 Image created by Sean Casey
At the start of the trial, both groups had similar responses to the meal tolerance test (MTT) as well as HbA1C.6 However, when assessed 12 weeks later, those who received the creatine saw significantly better improvements in acute blood sugar control in response to the MTT. Furthermore, as shown in Figure 2, those receiving creatine experienced a 1.1% decrease HbA1C levels, whereas no changes were experienced in the control group. For reference, no significant differences were noted between or within groups with respect to kcal or macronutrient intake throughout the 12 week study.
Figure 3. Decrease in HbA1C scores with creatine vs. metformin. Data adapted by Gualano et al,6 Saenz et al. who showed a 0.86% decrease,7 and Hirst et al who found a 1.12% decrease in HbA1C.8 Image created by Sean Casey.
As discussed in the preceding paragraph, creatine use was shown to decrease HbA1C by 1.1%. How does this compare to metformin, one of the most popular type II diabetes drugs on the market you ask? As shown in Figure 3 various meta-analyses have found metformin, in doses between 1-3 grams, lowers HbA1C levels between 0.86-1.12%.78 In other words, the participants in Gualano et al's study who received creatine (in addition to their normal treatment), experienced a greater drop in HbA1C levels (1.1%) vs. that expected by taking metformin in isolation or in addition to traditional therapy.
Fortunately, creatine and metformin do not "compete" to the point where they negate the other's benefit as shown in the above study. Metformin is believed to improve blood glucose management primarily though decreasing the liver's release of glucose (from the liver's glycogen stores) into the bloodstream and increasing glucose sensitivity at the skeletal muscle level.910 In contrast, creatine works primarily through increasing glucose uptake by the muscle cells; the latter of which will be discussed in greater detail later in this article. Thus, as my buddy Adel Moussa and I discussed prior to the publishing of this article, these characteristics make them a potent stack for those with diabetes.
Kidney Health & Creatine Supplementation in Type II Diabetics
Despite some concern that creatine may negatively affect kidney health (stemming from a few early case reports), there has yet to be any clinical trial to indicate this holds true in healthy individuals. As reviewed in the aforementioned ISSN Position Statement (please see hyperlink), multiple studies have shown that both acute and chronic creatine intake are safe. However, diabetics are at a greater risk to suffer kidney damage (vs. non-diabetic) related to elevated blood sugar levels. In fact, this is one of the primary concerns in those with diabetes. Thus, despite research indicating a lack of negative effects in a healthy population, its easy to see where one could hypothesize that creatine supplementation may be deleterious in diabetic populations. Is this concern warranted?
Fortunately for us, Gualano et al examined the creatine-diabetes-kidney health relationship. Using the same population mentioned above (type II diabetics without any pre-existing kidney issues), his research team examined various measures of kidney health including creatinine clearance, serum and urinary urea, electrolytes, proteinuria, and albuminuria.15 Following the 12 week supplementation period, Gualany et al, failed to find any changes in these variables leading them to conclude…
"… we demonstrated that CR supplementation does not impair kidney function in type 2 diabetic patients who underwent exercise training, opening a window of opportunities to explore its promising therapeutic role in this population…"
To date, this is the only randomized clinical control trial to my knowledge that has examined this relationship.
Will Creatine Supplementation Assist Blood Glucose Management in Healthy Individuals?
The above news is definitely exciting. That said, I realize that many of the individuals reading this are not diabetic. Thus, I'm sure you're probably asking yourself is, "Can healthy individuals who exercise 3-5 days/wk expect to see improvements in blood glucose management similar to what diabetics saw (i.e. – go from healthy blood-glucose to "super" healthy blood-glucose management)? Unfortunately, this question is something we can only speculate about for now. The effects of creatine on HbA1C levels in healthy populations has not formally been examined. [Although it may make for an interesting ME-search N=1 study for someone with the means.] However, various lines of research, indirectly tying into this question, may allow us to hypothesize on creatines impact on HbA1C/blood glucose management in non-diabetic populations…
Based off current research, it's known that creatine increases muscle glycogen stores in healthy individuals following a training session or when taken in conjunction with a multi-week training program.2311 Additionally, there has been one study which has examined creatine's impact on measures of acute blood glucose management. In it, Gualano et al, randomly assigned 22 previously sedentary healthy males to a creatine (0.15g/kg/day; ~10g/day for the average participate) or placebo group for a period of 12 weeks.12 During this same time period, all individuals completed an aerobic exercise program that consisted of 40 minutes of treadmill running 3x/wk at 70% VO2max. Oral glucose tolerance test (OGTT) as well as measures of insulin sensitivity were performed at weeks 0, 4, 8, 12. At the end of the study, no significant differences existed between groups with respect to insulin sensitivity or fasting insulin levels. The research team did report better glucose tolerance in the group receiving the creatine supplementation. However, the physiological relevance of it, as it relates to cardiometabolic health, was relatively small.
Thus, if you are healthy and highly active, the main benefit of creatine is via its ergogenic role (improved glycogen and phosphocreatine levels) rather than necessarily giving you "super human" blood glucose management.
Creatine Has Some Cool Effects on Glucose Storage for All & Blood Sugar Management for Diabetics ….. But How?
Figure 4. Changes in the ratio of ATP and ADP as a result of creatine phophorylation
AMPK – Where Have We Heard That Before? More than likely you recognize it from the fine work of Adel Moussa at SuppVersity as he wrote a nice article discussing the basics of AMPK as well as a nice follow-up article about the two forms of it. With blood glucose management on the brain, while their be sure to check out his excellent series on maintaining and improving your insulin sensitivity.
In order to understand how creatine is exerting its beneficial effects, we must first briefly review glucose uptake in muscle cells…Glucose is absorbed from the bloodstream into the muscles via a glucose transporter known as GLUT-4. In other words GLUT-4 acts as a "gatekeeper", allowing glucose to enter a given muscle; thus removing it from the blood stream. Within a given muscle cell, GLUT-4 can only be found in two different compartments; along the outer membranes (where it acts in a "gatekeeper" fashion) as well as floating within the cytoplasm.
Although creatine does not increase the amount of GLUT-4 within a cell, it does appear to increase the translocation (i.e. – movement) of GLUT-4 from a cell's cytoplasm to its outer membrane.6 This takes place as the additional creatine within the cell alters the ADP/ATP ratio, causing it to increase as ATP loses a phosphate group to creatine as shown in Figure 4. This increase in ADP (relative to ATP) leads to a greater expression of AMPK, a protein that acts as the "energy sensor" within the cell. In order to replace the energy lost via converting creatine into phosphocreatine, AMPK kicks off a process which eventually "tells" GLUT-4 receptors within the cytoplasm to journey over to the cell membrane.13 Once embedded in the outer walls, they can fulfill their role as the cell's gatekeepers "ushering in" new glucose molecules which will eventually be broken down for energy (1 glucose molecule generates 38 high energy ATP molecules).
[For those wondering, "yes" this is the same reason as to why exercise leads to improved glucose management]
Bottom Line
Creatine is often the ergogenic nutraceutical of choice for those individuals participating in high intensity anaerobic activities. However, its effects extend far beyond simply "increasing your squat", "improving your vertical jump" and/or shaving a little time off your sprint performance. As shown in this article, creatine is a beneficial supplement for those with poor glycemic control. Based off the study by Gualano et al. its effects were similar or greater than what is commonly observed when adding metformin into a blood glucose management program for diabetic individuals.
Now, I would be at fault if I didn't emphasize that the HbA1C results are only based off one small, relatively short term (12 weeks) study of creatine and we're yet to see if creatine has this same effect for diabetics in the absence of exercise. However, between this study, as well as a solid physiological mechanism, I see strong potential for this novel role of creatine in blood glucose management!
With respect to healthy individuals, it may slightly increase blood glucose management. However, its results are not likely physiological relevant. That said, it does assist with pumping up muscle glycogen levels, thus pumping up your muscle size a bit… So, I guess in the end, at least with respect non diabetic trainees, I failed to go "Beyond the Brawn" in writing this article on creatine – Oh well!
Reference
1 Buford TW, Kreider RB, Stout JR, Greenwood M, Campbell B, Spano M, Ziegenfuss T, Lopez H, Landis J, Antonio J. International Society of Sports Nutrition position stand: creatine supplementation and exercise. J Int Soc Sports Nutr. 2007 Aug 30;4:6.
2 Robinson TM, Sewell DA, Hultman E, Greenhaff PL. Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol (1985). 1999 Aug;87(2):598-604.
3 Nelson AG, Arnall DA, Kokkonen J, Day R, Evans J.Muscle glycogen supercompensation is enhanced by prior creatine supplementation. Med Sci Sports Exerc. 2001 Jul;33(7):1096-100.
4 van Loon LJ, Murphy R, Oosterlaar AM, Cameron-Smith D, Hargreaves M, Wagenmakers AJ, Snow R. Creatine supplementation increases glycogen storage but not GLUT-4 expression in human skeletal muscle. Clin Sci (Lond). 2004 Jan;106(1):99-106.
5 Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J Neurosci. 2000 Jun 15;20(12):4389-97.
6 Gualano B, DE Salles Painneli V, Roschel H, Artioli GG, Neves M Jr, De Sá Pinto AL, Da Silva ME, Cunha MR, Otaduy MC, Leite Cda C, Ferreira JC, Pereira RM, Brum PC, Bonfá E, Lancha AH Jr.
Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Med Sci Sports Exerc. 2011 May;43(5):770-8.
7 Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005 Jul 20;(3)
8 Hirst JA, Farmer AJ, Ali R, Roberts NW, Stevens RJ.Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care. 2012 Feb;35(2):446-54.
9 Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012 Mar;122(6):253-70.
10 Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002 Jul;51(7):2074-81.
11 Op 't Eijnde B, Ursø B, Richter EA, Greenhaff PL, Hespel P.Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes. 2001 Jan;50(1):18-23.
12 Gualano B, Novaes RB, Artioli GG, Freire TO, Coelho DF, Scagliusi FB, Rogeri PS, Roschel H, Ugrinowitsch C, Lancha AH Jr. Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids. 2008 Feb;34(2):245-50.
13 Alves CR, Ferreira JC, de Siqueira-Filho MA, Carvalho CR, Lancha AH Jr, Gualano B. Creatine-induced glucose uptake in type 2 diabetes: a role for AMPK-α? Amino Acids. 2012 Oct;43(4):1803-7. Epub 2012 Feb 17. Amino Acids. 2012 Oct;43(4):1803-7. Epub 2012 Feb 17.
14 Ben Mills and Jynto.Ball and stick model of the creatine molecule.Derivative of File:Phosphocreatine-3D-balls.png. 5 February 2010. Image accessed Dec 9, 2013 from:http://en.wikipedia.org/wiki/File:Creatine-3D-balls.png
15 Gualano B, de Salles Painelli V, Roschel H, Lugaresi R, Dorea E, Artioli GG, Lima FR, da Silva ME, Cunha MR, Seguro AC, Shimizu MH, Otaduy MC, Sapienza MT, da Costa Leite C, Bonfá E, Lancha Junior AH. Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial. Eur J Appl Physiol. 2011 May;111(5):749-56.