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Research ArticleThe Effects of Hyperhydrating Supplements Containing Creatine and Glucose on Plasma Lipids and Insulin Sensitivity inEndurance-Trained Athletes

Thelma P. Polyviou,1 Yannis P. Pitsiladis,2 Carlos Celis-Morales,3 Benjamin Brown,1

John R. Speakman,4 and Dalia Malkova 1

Human Nutrition, School of Medicine, College of Medicine, Veterinary and Life Sciences, New Lister Building,

Glasgow Royal Inrmary, - Alexandra Parade, Glasgow G ER, UK FIMS Reference Collaborating Centre of Sports Medicine for Anti-Doping Research, University of Brighton, Welkin House, Carlisle Road, Eastbourne BN SN, UK

BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular & Medical Sciences, University of Glasgow,Glasgow G A, UK

Institute of Biological and Environmental Sciences, University of Aberdeen, Zoology Building, illydrone Avenue, Aberdeen AB Z, UK

Correspondence should be addressed to Dalia Malkova; [email protected]

Received January ; Revised May ; Accepted May

Academic Editor: Hari Shanker Sharma

Copyright © Telma P. Polyviou et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Te addition o carbohydrate (CHO) in the orm o simple sugars to creatine (Cr) supplements is central. Te study aimed todetermine whether ingestion o glucose (Glu) simultaneously with Cr and glycerol (Cr/Gly) supplement is detrimental to plasmalipids o endurance-trained individuals and nd outwhether modication arising can be attenuated by replacing parto the Glu withalpha lipoic acid (Ala). wenty-two endurance-trained cyclists were randomized to receive Cr/Gly/Glu (. g Cr-H

2O, g Gly/kg

BM, and g Glu) or Cr/Gly/Glu/Ala (. g Cr-H2O, g Gly/kg BM, g Glu, and g Ala) or days. Fasting concentration o

AG increased signicantly (P < .) afer supplementation with Cr/Gly/Glu (beore: . ± . mmol/L; afer: . ± . mmol/L)and Cr/Gly/Glu/Ala (beore: . ± . mmol/L; afer: . ± . mmol/L) but changes were not different between the groups.Supplementation signicantly (P < .) increased the AG to HDL-cholesterol ratio but had no effect on asting concentrationo total, HDL-, and LDL-cholesterol and insulin resistance. Tus, addition o Glu to Cr containing supplements enhances plasmaAG concentration and the AG to HDL-cholesterol ratio and this enhancement cannot be attenuated by partial replacement o Glu with Ala.

1. Introduction

Creatine (Cr) is a guanidine compound which is naturally synthesised in the liver, kidney, and pancreas rom aminoacids arginine, glycine, and methionine []. Cr can also beobtained through diet, especially rom meat and sh [].Dietary Cr is taken up to tissues, including skeletal muscle[].Enhancement in muscle Cr content acilitates growth in leanbody mass, strength, and high intensity exercise perormance[]. It also enhances uid retention andprovides theimprove-ment in thermoregulation during exercise in the heat [, ].

As a consequence o these ndings, Cr supplementationhas become popular amongst recreational and proessionalathletes.

In vitro [] and in vivo [] studies demonstrated that Cruptake by rat skeletal muscle is increased by the presence o insulin. In humans, carbohydrate (CHO) ingestion, aimed atrising plasma insulin concentration, has been demonstratedto enhance both whole body Cr retention [] and skeletalmuscle Cr accumulation []. It has been suggested thatmuscle Cr accumulation is maximised when ∼ g o simplesugars is ingested with a typical g dose o Cr supplement

Hindawi Publishing CorporationJournal of Amino AcidsVolume 2015, Article ID 352458, 8 pageshttp://dx.doi.org/10.1155/2015/352458

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Journal o Amino Acids

[]. Te amount o Glu required can be expected to increaseavailable CHO intake above the habitually consumed level.Saety o such a high CHO intake while applying Cr supple-mentation protocols has not been investigated yet.

Some studies have demonstrated that increase in CHOintake may have detrimental impact on concentration o

plasma lipids not only in sedentary [–] but also inwell-trained individuals [–]. For example, in distancerunners consumption o a high CHO diet or two weeksincreased concentration o plasma triglycerides (AG) andtotal and LDL-cholesterol and reduced concentration o HDL-cholesterol []. Tese results were supported by another study which examined the effects o -week highCHO diet on plasma lipids in endurance-trained cyclistsand ound a signicant increase in plasma concentration o total cholesterol and AG []. A recent study also showedthat in trained males afer days on diet providing %o energy rom CHO, plasma concentration o AG wasincreased and concentration o HDL-cholesterol decreased[]. Based on population studies, these changes would beexpected to increase the risk o coronary heart disease[].

Due to these possible detrimental changes in plasmalipids induced by high glucose (Glu) intake consumed withCr containing supplements, there has been a search oralternative agents that stimulate insulin secretion and thusmay be expected to enhance skeletal muscle Cr uptake. Wepreviously demonstrated that the same increase in total body water and improvement in thermoregulatory and cardiovas-cular responses during exercise in the heat can be achievedwhen part o the Glu in the Cr/glycerol (Gly) hyperhydratingsupplement is replaced with alpha lipoic acid (Ala) [],a compound that has insulin-potentiating activity []. Itremains unclear whether expected changes in plasma lipidscan be attenuated by partial replacement o Glu with Ala.

Tis study aimed to determine whether ingestion o Glusimultaneously with Cr/Gly supplement is detrimental tothe asting concentration o plasma AG and the AG toHDL-cholesterol ratio, an independent risk actor o car-diometabolic risk [, ] o endurance-trained individuals,and nd out whether modications arising rom Cr/Gly/Glusupplementation can be attenuated by replacing part o theGlu with Ala (Ala).

2. Methods

.. Participants. wenty-two healthy endurance-trainedmales took part in the study. Physical characteristics o theparticipants are presented in able . Eligibility was assessed

via an interview and a medical questionnaire. During theinterview, the investigator conrmed that participants hadnot been supplemented with Cr – weeks preceding thestudy, as this was an exclusion criterion. Nevertheless,the act that previous Cr supplementation would act asan exclusion criterion was withheld rom the partici-pants. Upon recruitment, two participants were excludedrom the Cr/Gly/Glu group as asting plasma triglycerideconcentration exceeded recommended healthy concentra-tion o

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: Daily intake o creatine (Cr), glycerol (Gly), and glucose(Glu) andalpha lipoicacid (Ala) in Cr/Gly/Glu and Cr/Gly/Glu/Alagroups.

CR Gly Glu Ala

Cr/Gly/Glu (g) g/kg/BM (g) —

Cr/Gly/Glu/Ala (g) g/kg/BM (g) (mg)

the scales and how to complete properly the diaries weregivento each participant individually. Participants wereaskedto record the amount o all the ood and drinks consumedand report the time o consumption. Tey were also asked torecord the amount o all ood and drink which was lef afereating. Te dietary records were analysed or macronutrientand energy intake using dietary analysis sofware Windiets (Te Robert Gordon University, Aberdeen, Scotland,UK). Amount o CHO provided by the supplements wasadded to amount o CHO provided by the diet. Since Gly is dened by the US Food and Drug Administration (FDA)

as a CHO providing .kcal per gram, this was takeninto consideration when calculating the amount o CHOconsumed in the supplementation study.

... Blood Collection, Plasma Preparation, and Analysis.Subjects reported to the laboratory afer an overnight -hour ast. On arrival to the laboratory subjects were askedto lay comortably in a supine position or the duration o minutes and then venous blood sample was collectedin K

3EDA tube (BD, Vacutainer System, Franklin Lakes,

NJ, USA). ubes containing blood sample were immediately placed on ice and then centriuged or minutes at rpm(Hettich D- Universal R Centriuge, uttlingen,Germany). Plasma was dispensed in . mL aliquots intolabeled sterilised microcentriuge cap tubes (red microcen-triuge tubes with cap, FR, Fischer Scientic, UK) andkept at −∘C until analyses.

Plasma concentration o AG and total and HDL-cholesterol was analyzed by enzymatic colorimetric meth-ods using commercially available kits (Roche DiagnosticsGmbH, Mannheim, Germany). Plasma concentration o LDL-cholesterol was calculated using the Friedewald equa-tion []. Glu was assayed using the hexokinase method,utilising a Roche kit (Roche Diagnostics GmbH, Mannheim,Germany). Glu, AG, and total and HDL-cholesterol assayswere perormed on a Cobas Mira Plus (ABX Diagnostics,

France). All samples or each participant were analysed induplicate. Te accuracy and precision o the assays wasmonitored using quality control sera (Roche DiagnosticsGmbH, Mannheim, Germany; Randox Laboratories Ltd.,Co., Antrim, Ireland; Kamiya Biomedical, Seattle, USA).Te coefficients o variation were

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: Averaged daily energy, carbohydrate (CHO), at, andprotein intake in Cr/Gly/Glu and Cr/Gly/Glu/Ala groups beore(habitual diet) and during days o supplementation. Values aremean ± SD.

Cr/Gly/Glu Cr/Gly/Glu/Ala

Beore During Beore During

Available CHO (g) ± ± ∗ ± ± ∗

Sugar (g) ± ± ∗ ± ± ∗

NMES (g) ± ± a ± ± a

Starch (g) ± ± a ± ± a

Fibre (g) ± ± ± ±

Fat (g) ± ± a ± ± a

Protein (g) ± ± ± ±

Available CHO(g/kg/BM)

± ± ∗ ± ± ∗

Energy (MJ/day) ± ± ∗ ± ± ∗

From CHO (%) ± ± ∗ ± ± ∗

From at (%) ± ±

a

± ±

a

From protein (%) ± ± ± a ±

Note: NMES: non-milk extrinsic sugars. ∗Signicantly ( < 0 .0 1) higherthan beore; a signicantly ( < 0.01) lower than beore.

calculated by adding amount o Glu and Gly provided by supplements, was signicantly ( < 0.01) higher duringsupplementation than during the presupplementation week but supplementation had no effect on body mass in theCr/Gly/Gly (beore: 70.0 ± 5.8 kg; afer: 71.2 ± 5.3 kg, >0.05) and the Cr/Gly/Glu/Ala (beore: 78.0 ± 8.5 kg; afer:79.2±8.4 kg, > 0.05) groups. On the other hand both typeso supplementation induced signicant ( < 0.05) increasein BW (Cr/Gly/Gly: 1.7 ± 1.1 L; Cr/Gly/Glu/Ala: 1.2 ± 0.5 L, < 0.05) and the increase in BW tended ( = 0.40, = 0.06) to correlate with the changes in body mass.

Fasting concentration o plasma lipids is presented inFigure . Te concentration o AG and total, LDL-, andHDL-cholesterol measured beore supplementation was notsignicantly different between groups. Fasting concentrationo plasma AG increased signicantly ( < 0.01) afer sup-plementation with Cr/Gly/Glu (beore: 0.90 ± 0.19 mmol/L;afer: 1.30 ± 0.44 mmol/L, < 0.01) and Cr/Gly/Glu/Ala(beore: 0.77 ± 0.25 mmol/L; afer: 1.2 ± 0.54 mmol/L, <0.01). Te AG to HDL-cholesterol ratio increased signi-

cantly ollowing supplementation with Cr/Gly/Glu (beore:0.5 ± 0.07; afer: 0.8 ± 0.19; = 0.01) and Cr/Gly/Glu/Ala(beore: 0.5 ± 0.1; afer: 0.8 ± 0.2; = 0.002). Teincrease in plasma AG concentration and in the AG toHDL-cholesterol ratio was not signicantly different betweengroups. Supplementation had no effect on asting concentra-tion o total, HDL-, and LDL-cholesterol.

Beore supplementation, the concentration o asting Gluand insulin and insulin resistance evaluated rom HOMA

IR

were not signicantly different between Cr/Gly/Glu andCr/Gly/Glu/Ala groups. None o the supplements had impacton plasma Glu or insulin concentrations and HOMA

IR

(able ).

: Plasma concentration o asting glucose and insulin, andhomeostasis model assessment o insulin resistance (HOMAIR ) pre-ceding supplementation (Pre) and afer days o supplementation(Post). Values are means ± SD.

Cr/Gly/Glu Ala /Cr/Gly/Glu

Pre Post Pre Post

Glucose (mmol/L) . ± . . ± . . ± . . ± .

Insulin (lU/mL) . ± . . ± . . ± . . ± .

HOMAIR . ± . . ± . . ± . . ± .

4. Discussion

Tis study ound that -day supplementation o endurance-trained individuals with hyperhydrating Cr/Gly supplementcontaining either or g o Glu signicantly increaseddaily intake o available CHO and induced increase inasting concentration o plasma AG and the AG toHDL-cholesterol ratio, an independent risk actor o car-diometabolic risk [, ]. We also ound that these changescannot be attenuated by replacing g o Glu with Ala,another insulinotropic compound, required to promote Cruptake by the skeletal muscle. We note that in endurance-trained athletes modied AG concentrations remainedbelow the unhealthy range [] and suggest that increasedintake o CHO during Cr supplementation doesnot representa deleterious effect on cardiometabolic risk. However, in lesstrained individuals or habitual gym users ofen Cr loadingwhen combined with Glu or other orms o simple sugars canbe expected to increase plasma AG concentration and theAG to HDL-cholesterol ratio to higher levels. Te latter issolely an extrapolation rom our ndings and may be worth

investigating through uture studies.Our nding is that seven-day consumption o Cr based

supplements containing Glu increased concentration notonly in sedentary [–] but also in endurance-trainedathletes. Plasma concentration o AG is in consistency with the previous evidence showing that, in trained indi-

viduals, short-term enhanced CHO intake leads to signi-icant increase in asting plasma AG concentrations [–]. Te AG to HDL-cholesterol ratio, an independentrisk actor o cardiometabolic risk [], has also increasedsignicantly ollowing supplementation with Cr/Gly/Glu andwith Cr/Gly/Glu/Ala. Tus, our ndings contribute to thenotion that, regardless o endurance training being associated

with efficient metabolism o plasma AG and prolongedsurvival o HDL lipoproteins [], endurance athletes cannotwithstand the impact o acutely enhanced CHO intake. Tus,modication o macronutrient composition o the diet due toincreased CHO intake enhances plasma AG.

Previous studies show that Ala, a naturally existingcompound that acts as a coenzyme or pyruvate dehydroge-nase and -ketoglutarate dehydrogenase, plays a key role inbridging glycolysis and the citric acid cycle and regulates Gluand lipid metabolism and has insulin-potentiating activity []. Tus, this study also aimed to nd out whether changeso plasma lipids induced by Cr supplementation protocols,considering CHO addition, can be prevented or at least

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T A G ( m

m o l / L )

T o t a l c h o l e s t e r o l ( m m o l / L )

0

2

4

6

8


0

2

4

6

8

Cr/Gly/Glu Cr/Gly/Glu/Ala0

2

4

6

8


0

2

4

6

8


L D L - c h o l e s t e r o l ( m m o l / L )

H D L - c h o l e s t e r o l ( m m o l / L )

∗∗

Pre

Post

Pre

Post

F : Fasting concentrations o plasma lipids at baseline (Pre) are represented with white bars and afer days o supplementation (Post)

represented with black lled bars ∗

Signicantly different ( < 0.05) rom presupplementation in corresponding group. Values are presentedas means ± SD.

attenuated when grams o Glu is replaced with Ala. Weound that the extent o increase in plasma concentrationo AG was not signicantly different between the groupconsuming and the group consuming g Glu plusAla. Tis is not surprising since increase in CHO intakewas signicant and associated with reduction in at intake inboth groups. Tus, in both groups, diets consumed duringthe seven days o the supplementation period were highCHO/low at diets and differ signicantly rom habitual

diets. Our data suggest that diminishing daily Glu intakeby g and replacing that amount o Glu with Ala cannotprevent increase in plasma concentration o AG induced by incorporation o Glu.

Prior supplementation plasma concentration o AG waslow and within a range o .–. and .–. mmol/L in theCr/Gly/Glu and Cr/Gly/Glu/Ala groups, respectively, whichis in agreement with other studies investigating lipid proleso trained individuals []. Afer days o consumption o both supplements, plasma AG concentration was still below . mmol/L, a concentration which is known to have a detri-mental impact on distribution o LDL subtractions, leadingto the increase in proportion o LDL

3 particles [], the most

atherogenic lipoprotein particles. In addition, regardless o other studies reporting that, in athletic individuals, increasein plasma AG leads to a synergistic decrease in HDL-cholesterol [–] the present study ound that, afer dayso enhanced CHO intake, plasma concentration o HDL-cholesterol was not diminished. Tus, endurance-trainedindividuals with baseline concentration o plasma AG beingwithin healthy range [] should be sae to enhance intake o simple sugars required or promotion o muscle Cr uptake. In

addition, since AG-raising effect o high CHO is transientand disappears with time [], it could be suggested thatshort-term high intake o CHO should not be o any concernor healthy and well-trained individuals. Tis, however, may not be the case or less trained individuals such as habitualgym users who ofen combine Cr loading with enhancedintake o simple sugars and or sedentary overweight individ-uals in whom higher-CHO diets, particularly those enrichedin rened CHO, create a metabolic state that promotesdevelopment o atherosclerosis [, ].

From the athletes’ point o view increase in plasma AGconcentration ound afer both types o supplementation may be considered as benecial rather than detrimental change.

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Indeed, the increase in plasma AG concentration may beexpected to increase VLDL-derived atty acid availability andrateso atoxidation during exercise and thus have a potentialto slow the rate o glycogen utilization and delay the onseto atigue during sport competition and training []. Tishypothesis requires evaluation since in sedentary individuals

short-term adaptation to a high CHO diet induces metabolicalterations suggestive o repartitioning atty acids away romoxidation toward esterication in both liver and muscle[]. In addition, increase in plasma AG concentrationand the AG to HDL-cholesterol ratio due to Cr/Gly/Gluand Cr/Gly/Ala supplementation can be outweighed by theenhancement in muscle glycogen accumulation [] andexpansion o water compartments within the human body and thus attenuation in the rise in heart rate and reductionin thermal and cardiovascular strain during exercise in theheat without negatively impacting exercise economy [].

Based on the data obtained rom dietary records, weound that during the days o supplementation energy intakewas higher than habitual energy intake. Tus, it could beargued that supplementation induced increase in plasmaAG concentration was a consequence not only o enhancedCHO intake but also o change in energy balance. How-ever, both interventions had no signicant impact on body mass, which implies that energy intake, during interventions,was not different rom habitual energy intake. Tis impliesthat ood intake recording might have been more accurateduring supplementation days. Indeed, during interventionsparticipants were contacted by the researchers daily as ameans o enhancing compliance to interventions and alsoto remind participants to record ood and drink intake.It is also important to note that only long-term energy imbalance leading to weight gain was ound to be associatedwith an increase in plasma AG concentrations [], whileacute dietary energy surplus (∼ MJ) had no effect on basalVLDL-AG metabolism and thus asting AG concentration[]. Tese nding are in consistency with recent data []suggesting that disturbance in energy balance leading up tomore than kg o visceral at increase would be requiredto achieve changes in plasma AG concentration ound inour study. It is obvious that this increase in visceral or eventotal body at did not take place in the current study. Indeed,our data demonstrate that body weight changes i any wereexclusively related to the changes in BW. Tus, an increasein plasma AG concentration seen in both groups was mostlikely related to signicant and quite extensive changes in

macronutrient intake rather than changes in energy balance.We ound that insulin sensitivity as determined by

HOMAIR

was not affected by supplementation. Te expectedadverse effects o high CHO intake on insulin sensitivity [] could have been offset by the consumption o Cr andAla, which have previously been ound to improve insulinsensitivity. Ala supplementation has been shown to enhanceactivation o adenosine monophosphate activated kinase(AMPK), which subsequently enhanced insulin stimulatedGlu disposal and reduced asting insulin []. Similarly, Crsupplementation has been shown to improve Glu tolerance[] in healthy males undergoing aerobic training []. Itshould be noted that due to very high cardiorespiratory

tness, participants o this study had very low HOMAIR

[]and thus may have preserved insulin sensitivity regardless o high CHOintake. In addition there is evidence to suggest thatincreasing CHO intake improves rather than impairs glucosetolerance []. Tus, the adverse effects o acute increase inCHO intake on plasma lipid concentration canbe expected to

be balanced either by no effect or potentially by a avourableinuence on Glu tolerance. We appreciate that not usingthe gold standard technique, euglycemic hyperinsulinemicclamp, or the assessment o insulin sensitivity and consider-ing only asting concentrations o insulin and Glu might havelimited revealing impact on insulin and Glu dynamic.

5. Conclusion

In conclusion, in endurance-trained individuals, short-termincrease in available CHO intake, through the Cr/Gly/Gluhyperhydrating supplement which has been used prior toexercise in the heat, causes a signicant increase in plasma

AG concentration and the AG to HDL-cholesterol ratio.Tese detrimental changes cannot be attenuated by partialreplacement o Glu with insulin-potentiating agent such asAla. Tese ndings should be o potential interest not only toscientists but also to athletes, coaches, and sports dietitians.

Conflict of Interests

Te authors declare that they have no competing interests.

Authors’ Contribution

Telma P. Polyviou assisted in the design o the study, subject

recruitment, study management, data collection, and analysisand was the primary author o the paper. Yannis P. Pitsiladisconceivedo the studyand participatedin itsdesign andcoor-dination. John R. Speakman and his team at the University o Aberdeen carried out measurements o BW. Carlos Celis-Morales was involved in subject recruitment, data collection,and analysis. Dalia Malkova assisted in study supervision andcoordination and was involved in data analysis and helped todraf the paper. All authors read andapproved the nalpaper.

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