Oxidation of Carbohydrate Feedings During Prolonged Exercise Current Thoughts, Guidelines and Directions for Future Research

Sports Med 2000 Jun; 29 (6): 407-424 REVIEW ARTICLE 0112-1642/00/0006-0407/$20.00/0

Asker E. Jeukendrup and Roy Jentjens Human Performance Laboratory, School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham, England

Contents Abstract ...... 407 1. Methodological Considerations ...... 408 1.1 Radioactive Isotopes ...... 409 1.2 Stable Isotopes ...... 409 2. Feeding Strategies and Exogenous Carbohydrate (CHO) Oxidation ...... 410 2.1 Feeding Schedule ...... 410 2.2 Types of CHO ...... 411 2.2.1 Fructose ...... 411 2.2.2 Galactose ...... 412 2.2.3 Maltose ...... 412 2.2.4 Sucrose ...... 413 2.2.5 Glucose Polymers – Maltodextrins ...... 413 2.2.6 Starch ...... 413 2.2.7 Summary ...... 414 2.3 Multiple Transportable CHOs ...... 414 2.4 Osmolality and Concentration ...... 415 2.5 Amount of CHO ...... 415 3. Factors Affecting Exogenous CHO Oxidation ...... 416 3.1 Exercise Intensity ...... 416 3.2 Muscle Glycogen ...... 417 3.3 Training ...... 418 4. Limitations of Exogenous CHO Oxidation ...... 419 5. Directions for Future Research ...... 421 6. Practical Implications, Guidelines and Conclusion ...... 422

Abstract Although it is known that carbohydrate (CHO) feedings during exercise improve endurance performance, the effects of different feeding strategies are less clear. Studies using (stable) isotope methodology have shown that not all carbohydrates are oxidised at similar rates and hence they may not be equally effective. Glucose, sucrose, maltose, maltodextrins and amylopectin are oxidised at high rates. Fructose, galactose and amylose have been shown to be oxidised at 25 to 50% lower rates. Combinations of multiple transportable CHO may increase the total CHO absorption and total exogenous CHO oxidation. Increasing the CHO 408 Jeukendrup & Jentjens

intake up to 1.0 to 1.5 g/min will increase the oxidation up to about 1.0 to 1.1 g/min. However, a further increase of the intake will not further increase the oxidation rates. Training status does not affect exogenous CHO oxidation. The effects of fasting and muscle glycogen depletion are less clear. The most remarkable conclusion is probably that exogenous CHO oxidation rates do not exceed 1.0 to 1.1 g/min. There is convincing evidence that this limitation is not at the muscular level but most likely located in the intestine or the liver. Intestinal perfusion studies seem to suggest that the capacity to absorb glucose is only slightly in excess of the observed entrance of glucose into the blood and the rate of absorption may thus be a factor contributing to the limitation. However, the liver may play an additional important role, in that it provides glucose to the bloodstream at a rate of about 1 g/min by balancing the glucose from the gut and from glycogenolysis/gluconeogenesis. It is possible that when large amounts of glucose are ingested absorption is a limiting factor, and the liver will retain some glucose and thus act as a second limiting factor to exogenous CHO oxidation.

The number of studies concluding that carbohy- The purpose of this review is not to review the drate (CHO) feedings during exercise improve ex- effects of CHO on exercise performance per se,but ercise capacity or exercise performance is so large to summarise the factors that determine the efficacy that, from a scientific point of view, we can con- (i.e. oxidation) of ingested CHO. With the conclu- sider this relationship true. In the last few years, sions from this overview, guidelines will be formu- studies have accumulated to show that CHO feed- lated for the use of CHO supplements during exer- ings during exercise can positively affect perfor- cise. Finally, some of the remaining questions and mance when the exercise duration is about 45 min- directions for future research will be discussed. utes or longer.[1,2] The mechanism by which these CHO feedings exert their effect is believed to be a 1. Methodological Considerations maintenance of blood glucose and increased rates of CHO oxidation during exercise.[2] It has also been TheoxidationofingestedCHOcanbemeasured [10] shown that CHO feedings during exercise ‘spare’ by using isotope techniques. Costill et al. were liver glycogen.[3-5] However, whether CHO feedings probably the first to study the oxidation of ingested CHO. They labeled the CHO in a drink with a ra- ‘spare’muscle glycogen is still controversial, as some dioactive tracer ([U-14C]glucose) and reported that studies reported glycogen ‘sparing’[6,7] whereas oth- only a small amount of an ingested CHO load was ers did not.[2,8] This debate has recently been re- [9] oxidised during exercise. As a result, they concluded viewed by Tsintzas and Williams. Several studies that CHO feedings were of limited importance for have also addressed the questions of which CHO was muscle metabolism. However, this result was prob- most effective, what the most effective feeding ably the result of methodological problems, since schedule was and the optimal amount of CHO to many studies in the following years have shown be ingested. Additional studies have looked at fac- significant contributions of ingested CHO to energy tors that can possibly influence the oxidation of expenditure during exercise. Most studies today use ingested CHO, such as muscle glycogen levels, diet, stable isotopes for the measurement of exogenous and exercise intensity. More recently, studies have CHO oxidation, since this does not provoke any attempted to detect the factors that limit the maxi- health hazards in contrast to the potential negative mal rates of exogenous CHO oxidation. effects of radioactive isotopes. The advantages and

disadvantages of these techniques will be discussed In many experimental conditions, the entrapment 14 13 in sections 1.1 and 1.2. of CO2 or CO2 in the bicarbonate pool may cause a marked underestimation of the true exogenous 1.1 Radioactive Isotopes CHO oxidation, especially during the first hour of exercise. The oldest method to trace ingested CHO is to There are a few ways around this problem. One 14 add a [U- C]glucose tracer to a CHO beverage and way is to prime the bicarbonate pool with H14CO – 14 3 measure C in expired gases using a scintillation 13 – or H CO3 . This would bring the bicarbonate pool counter. The advantage of this technique is that it into equilibrium within the first 15 minutes of ex- is relatively inexpensive compared with the use of ercise.[5,8] A second way is to avoid calculating ex- stable isotopes. In addition, shifts in background ogenous CHO oxidation rates in the first hour.[14] enrichments which may occur when using stable Finally, it is possible to use an acetate correction isotopes (see section 1.2) are not a problem, be- factor as suggested recently.[15] In addition to the 14 cause the background level of C is negligible. temporary label loss in the bicarbonate pool, it has An obvious disadvantage of this technique is the also been reported that, in studies using a 13C-tracer fact that it exposes the volunteer to radioactivity. for studying fatty acid metabolism, part of the tracer Although the radiation dose given is usually low may be trapped in exchange reactions with the tri- (<40 uCi/L is consumed), and is calculated to cor- carboxylic acid (TCA)-cycle.[15,16] For example, respondto0.02to0.03rem,200to250timeslower some 13C-carbons may be incorporated into the glu- than the permissible dose, the actual risks may of- tamate/glutamine pool via α-ketoglutarate (α-KG), [11] ten be underestimated. Glucose is not only used or into phosphoenolpyruvate (PEP) via oxaloace- for oxidation, but is also a substrate for other me- tate (OAA).[16] This label fixation results in a de- tabolic pathways, including pathways that result in creased recovery of label in the expired gases and, the formation of DNA. Incorporation of radioac- in order to correct for this loss, the acetate correc- tivity in a DNA molecule is of course dangerous tion factor has been proposed.[15] This correction because it may damage genetic material. It is there- is based on the assumption that acetate has immediate fore advisable to use stable isotopes rather than access to the TCA-cycle and is instantly oxidised. radioactive isotopes to study metabolism. The percentage of label (13Cor14C) not recovered One potential problem with using isotopes (ra- in expired CO2 represents the amount of CO2 dioactive or stable) is that part of the CO2 (includ- trapped in exchange reactions with TCA-cycle in- 14 13 ing CO2 or CO2) may not appear in the expired termediates (TCAI) and the bicarbonate pool. The gases because it is temporarily trapped in the bicar- label loss is dependent on the metabolic rate. At bonate pool. high oxygen uptakes (>35 ml/kg/min) less label is – + trapped and recovery of the 1-14C-acetate label was CO2 +H2O ↓à H2CO3 ↓à HCO3 +H (Eq. 1) foundtobe85to90%.[15] Similar results were ob- Thisisaverylargeandonlyslowlyexchanging tained by Schrauwen et al.[16] when [U-13C]palmi- pool, in which CO2, arising from various decarbox- tate was used. This implies that studies performed ylation reactions, is retained. In resting conditions, at low absolute exercise intensities may have under- it may take hours before there is an equilibrium estimated exogenous CHO oxidation rates. 14 14 – 13 13 – between CO2 and H CO3 (or CO2 and H CO3 ). However, during exercise the turnover of this pool 1.2 Stable Isotopes increases severalfold and, especially at high absolute workloads, equilibrium may be reached within 60 Studies in which stable isotope methodology 13 minutes. It has been reported that recovery of CO2 was used to measure exogenous CHO oxidation 13 approached 100% after 60 minutes. of exercise at have used C-enriched substrates. Some of these [10,12,13] 60 to 70% maximal oxygen uptake (VO2max). studies have used naturally enriched CHO (derived

from C4 plants such as corn and cane sugar). These can then be used to correct the calculated exoge- plants have a naturally high abundance of 13C. nous CHO oxidation. When ingesting these CHOs during exercise, breath . Exogenous CHO oxidation = VCO • (ECO – 13CO will become enriched and, together with a 2 2 2 Ebkg)/(Eing – Ebkg) • 1/k (Eq. 2) measure of the total CO2 production rate, exoge- . nous CHO oxidation rates can be quantified. In ad- where VCO2 is the total CO2 production rate, ECO2 13 13 dition to the problems described above, there is an- is the C-enrichment of CO2,Eingisthe C- other complication with this technique: shifts in enrichment of the ingested CHO, Ebkg is the back- substrate utilisation may result in a change in background enrichment determined in a separate exper- ground enrichment.[17,18] Because CHO is usually iment with the same conditions, and k is the amount more 13C-enriched than fat, glycogen stores may of CO2 that will arise from the oxidation of 1g of display higher 13C-enrichments than endogenous glucose (0.7466L CO2/g glucose). fat stores. Any change in shift in endogenous sub- It is possible to obtain accurate and reliable measures of exogenous CHO oxidation using (ra- strate utilisation can therefore cause a change in the dioactive or stable) isotopes. However, as was just background 13C-enrichment independent of ingested discussed, there are several errors that can be made CHO. These changes occur for instance in the tran- andhavebeenmadeinthepast.Thisisimportant sition from rest to exercise, and typically an increase when interpreting results, especially from some of 13 in CO2 in the expired gases is observed. The mag- the earlier studies. The absolute values reported in 13 nitude of the error depends on the C-enrichment several trials may be overestimated in studies using 13 of the ingested CHO relative to the C-enrichment CHO with a naturally high 13C-abundance because of endogenous glycogen stores. It has been shown no corrections were made for background enrich- that individuals with a diet in which most CHOs ment. Other studies may have underestimated ex- are derived from C4 plants (a typical northern Amer- ogenous CHO oxidation because no correction was ican or Canadian diet) have higher 13C-enrichments made for label loss or label fixation. We would like in their muscle glycogen stores compared with Euro- the reader to keep this in mind when interpreting peans, whose diet is typically derived from C3 plants the results of various studies. Here, we will present such as potato and beet sugar. . the data of different studies as presented in the orig- In a comparative study at 60% VO2max at Ball inal papers. We have not tried to correct for the State University (Indiana, USA) and Maastricht Uni- possible methodological errors because there were versity (The Netherlands), we have observed that too many unknown variables (e.g. diet, background in northern America, shifts in background enrich- enrichments) and often papers did not report suffi- ment may be 3 to 5 times higher than in Europe cient information (e.g. enrichment data) to allow (unpublished data). Several investigators have there- these corrections to be made. Nevertheless, in most fore instructed their study participants not to con- cases the error will be small (5 to 10%) and correc- sume products with a high natural 13C-abundance, tion would not have altered the conclusions of these or have reduced the error by artificially increasing papers since typically 2 or 3 trials are compared in the same experimental conditions. the 13C-enrichment of the CHO ingested during the experiment (typically by adding [U-13C]glucose to 2. Feeding Strategies and Exogenous a CHO beverage). By adding a tracer to the CHO, Carbohydrate (CHO) Oxidation the shift in background remains the same but the relative error is reduced. Another way around the 2.1 Feeding Schedule problem is to perform control trials with an identical protocol but with ingestion of CHO with a low The typical pattern of exogenous glucose oxida- natural abundance. The background 13C-enrichments tion rates is shown in figure 1. The first appearance

of label from ingested CHO can already be ob- 1.2 served in the first 5 minutes (unpublished observa- HI-GLU tions). During the first 75 to 90 minutes of exercise, 1.0 exogenous CHO oxidation will continue to rise as 0.8 more and more CHO will be emptied from the 0.6 stomach and absorbed in the intestine. After 75 to 0.4 90 minutes a leveling-off will occur and the exog- 0.2 LO-GLU enous CHO oxidation rate will reach its maximum 0 0 30 60 90 120 value and will not further increase. The timing of (g/min) Exogenous CHO oxidation CHO feedings seemed to have very little effect on Time (min) the slope of this curve or the plateau value. In sev- Fig. 1. Typical pattern of exogenous carbohydrate (CHO) oxi- eral studies[19-23] the oxidation of a single glucose dation during exercise when beverages are consumed at the onset of exercise and at regular intervals thereafter. HI-GLU = load (100g) given at the onset of exercise (90 to high glucose ingestion; LO-GLU = low glucose ingestion. 120 minutes) was investigated. They all reported a very similar oxidation pattern for ingested glucose; an increase in oxidation rates during the first 75 to impact on the maximal exogenous CHO oxidation 90 minutes and a plateau thereafter. Maximal ex- rates or the time to reach this maximum. However, ogenous CHO oxidation rates in these studies var- the feeding schedule should be such that high exo- ied between 0.48 and 0.65 g/min. These rates are genous CHO oxidation rates are achieved as soon similar to those observed when ingesting similar as possible after the onset of exercise and the amount amountsofglucose(90to100gin90to120min- of CHO ingested should be sufficient to maintain utes) as repetitive feedings during exercise.[24-28] high rates of exogenous CHO oxidation. [32] In a study by Krzentowski et al.,[20] volunteers McConell et al. compared the effects of CHO . ingestion throughout exercise with ingestion of an walked at a 10% grade (45% VO ) for 4 hours. 2max equal amount of CHO late in exercise. In this study, They ingested 100g of glucose after 15 or 120 min- performance was improved relative to the control utes. Exogenous CHO oxidation rates followed an trial only when CHO was ingested throughout ex- identical pattern from the time of ingestion until 2 ercise. CHO ingestion late in exercise did not im- hours later. The amount of ingested glucose ox- prove performance despite increases in plasma glu- idised was similar in the 2 hours following inges- cose and insulin levels. tion (55g when CHO was ingested after 15 minutes and 54g when ingested after 120 minutes). This 2.2 Types of CHO study showed that the time of ingestion has no effect on exogenous CHO oxidation. Often repetitive In figure 2, different types of dietary CHO are feeding schedules are adopted because it has been depicted. Different types of CHO may have differ- shown that this accelerates the rate of gastric emp- ent properties. Differences in osmolality and struc- tying and hence the delivery of CHO to the intes- ture have effects on taste, digestion, absorption, the tine.[29,30] However, since gastric emptying does release of various hormones, and the availability not usually limit exogenous CHO oxidation,[27,31] of glucose for oxidation in the muscle. A number the feeding schedule may have little effect on the of studies have compared the oxidation rates of maximum oxidation rates or the time to reach these various types of ingested CHO with the oxidation [26,27,31,33-38] high rates of oxidation. Thus, although there are no of glucose during exercise. The results studies available that have directly studied the ef- will be discussed in the following sections. fect of different feeding schedules on the rate of 2.2.1 Fructose exogenous CHO oxidation, the literature seems to There has been considerable interest in fructose suggest that the feeding schedule has very little for a variety of reasons.[23,39,40] The first reason is

C OH Glucose Fructose Galactose

C C O OH OH Maltose Sucrose Lactose C C C OH OH

Amylopectin starch Maltodextrin Amylose starch Fig. 2. Overview of different carbohydrates and their structure. There are 3 monosaccharides (glucose, fructose and galactose) and 3 disaccharides (maltose, sucrose and lactose). Glucose polymers (maltodextrins) and starch consist of a series of coupled glucose molecules. that adding fructose will generally improve the pal- 2.2.2 Galactose atability of a drink. Secondly, fructose will cause a Only one study has investigated the oxidation 20 to 30% smaller increase in plasma insulin levels rates of ingested galactose during exercise. Leijssen [35] compared with glucose,[41] and hence it will reduce et al. fed. 8 volunteers, who exercised for 2 hours lipolysis to a smaller extent. Fructose has also been at 70% VO2max, 155g of galactose or glucose and used as a pre-exercise feeding to prevent exercise- calculated the oxidation rates of the exogenous CHO. induced rebound hypoglycaemia.[23,39,40] Massicotte While glucose was oxidised at a rate of 0.85 g/min and colleagues[26,33] studied the oxidation of fruc- during the last hour, galactose oxidation was only tose compared with an isoenergetic glucose solution half of that (0.41 g/min). It was suggested that the and found 25% lower oxidation rates for fructose. absorption or the conversion into glucose in the Jandrain et al.[42] studied exogenous CHO oxida- liver was limiting. Galactose on its own therefore tion rates in 10 healthy but untrained. volunteers seemed an inappropriate source of CHO for sports during 3 hours of exercise at 45% VO2max while drinks. ingesting 150g glucose or fructose. The peak oxidation rates for the ingested glucose were 0.67 g/min 2.2.3 Maltose [36] and fructose oxidation peaked at 0.50 g/min (25% Hawley et al. investigated the oxidation of lower). Similar findings were reported by oth- maltose and. glucose during 90 minutes of exercise ers.[23,34,43,44] The lower oxidation rates of fructose at 70% VO2max. Trained volunteers ingested 180g are probably due to a lower rate of absorption and of glucose or maltose during exercise and exogen- the fact that fructose has to be converted into glu- ous CHO oxidation was measured using radioactive cose in the liver before it can be metabolised. The isotopes. High peak oxidation rates were reached latter is usually a relatively slow process. Interest- at the end of exercise and equaled 0.9 g/min for ingly, during fasting when gluconeogenic pathways glucose and 1.0 g/min for maltose. These differ- are activated, similar rates of oxidation were found ences were not statistically significant and it was for glucose and fructose.[25,34] concluded that maltose and glucose are oxidised at

similar rates. In addition, these authors found no Table I. Amylose and amylopectin content of various plant starches differences in the absorption rates of these CHOs. Plant starches Amylose (%) Amylopectin (%) Maize 24 76 2.2.4 Sucrose Potato 20 80 Few studies have investigated the oxidation of Rice 19 81 ingested sucrose. In a study by Moodley et al.,[27] Tapioca 17 83 volunteers ingested 90g. of sucrose during 90 min- Wheat 25 75 utes of exercise at 70% VO2max. Sucrose oxidation rates peaked at approximately 0.4 g/min. Although these rates may seem quite low, similar oxidation Wagenmakers et al.[37] found similar results when rates were reported for glucose and the low values feeding volunteers maltodextrin solutions ranging may therefore be a result of the methodology used from 4 to 16%. Increasing rates of CHO ingestion in that study. Wagenmakers et al.[37] gave their seemed to increase oral CHO oxidation up to a rate study participants an 8% sucrose solution. during 2 of 1.0 to 1.1 g/min. Ingestion of more than 1.2 g/min hours of cycling exercise at 65% VO2max. The total had very little or no additional effect on the oxida- amount of sucrose ingested during the 2 hours was tion rates.[37] However, these high rates of inges- 145g, and it was estimated that 81g was oxidised. tion did result in high oral CHO oxidation rates The peak oxidation rate was 0.87 g/min, a value (0.53 to 1.07 g/min) that were similar to the rates similar to that observed after glucose ingestion in observed with glucose ingestion in other studies. other studies.[8,14,25-28,36,45] It can therefore be con- 2.2.6 Starch cluded that sucrose can be oxidised at similar rates There are 2 major types of starch: amylopectin as glucose and the efficacy of these 2 CHOs may and amylose. Amylopectin is a highly branched mol- be similar. ecule, whereas amylose is a long straight chain of 2.2.5 Glucose Polymers – Maltodextrins glucose molecules (fig. 2) twisted into a helical Because of their neutral taste and their relatively coil. Branches in starch are created by 1,6 bonds low osmotic value, maltodextrins have been used between glucose units, whereas 1,4 glucosidic bonds by many manufacturers of sports drinks to increase will result in a straight chain of glucose units. the CHO content of these beverages. In a study by Starches with a relatively large amount of amylo- Rehrer et al.,[31] a 17% maltodextrin solution was pectin are rapidly digested and absorbed, whereas compared with a 17% glucose solution. The total those with a high amylose content will have a slow amount of CHO that was ingested. during 80 min- rate of hydrolysis. Starches make up approximately utes of exercise at 70% VO2max was 220g. Oral 50% of our total daily CHO intake and most natu- CHO oxidation was measured and was found to be rally occurring starches are a mixture of amylose similar for the glucose and the maltodextrin drink and amylopectin (see table I). One study[38] com- (42 and 39g for glucose and maltodextrin, respec- pared the rate of gastric emptying and the oxidation tively). A peak oxidation rate of 0.78 g/min was rate of an insoluble starch consisting of 23% amy- reported for glucose and 0.75 g/min for malto- lose and 77% amylopectin with a soluble starch dextrins. These results indicate that there is no dif- consisting of 100% amylopectin. Volunteers ingested ference in the oxidation of maltodextrins and glu- 316g. during 2.5 hours of cycling exercise at 68% cose. In addition, it was found that the rates of VO2max. The amount of CHO delivered to the in- gastric emptying and thus the rate of delivery of testine seemed somewhat lower in the case of the CHO to the intestine was similar between glucose insoluble starch, but this difference did not reach and the glucose polymer. These results also imply statistical significance. However, the insoluble starch that the digestion (hydrolysis of the bonds between was oxidised at a lower rate (75g of insoluble starch glucose molecules of a glucose polymer) is not a compared with 126g of soluble starch). Peak oxi- rate-limiting step for exogenous CHO oxidation. dation rates were 1.1 and 0.8 g/min for the soluble

3 Glucose Fructose Galactose Sucrose Maltose MD Starch 2

1 Oral CHO oxidation rate (g/min) rate CHO oxidation Oral

0 0123 CHO ingestion rate (g/min) Fig. 3. Peak oxidation rates of oral carbohydrates (CHOs) are depicted against the CHO ingestion rate of different types of CHO. Fructose and galactose appear to be oxidised at relatively low rates whereas glucose, sucrose, maltose, maltodextrins and soluble starch seem to be oxidised at relatively high rates. The horizontal line depicts the absolute maximum for oral CHO oxidation. The dotted line represents the line of identity, where CHO ingestion equals CHO oxidation. starch and the insoluble starch, respectively, while high rates. Maximal oral CHO oxidation seems to the insoluble starch seemed to cause some gastro- be around 1 g/min. The horizontal line depicts the intestinal discomfort.[38] The oxidation of amylose absolute maximum just below 1.1 g/min. The dot- only was not measured but can be assumed to be ted line represents the line of identity, where CHO very low. Although one study reported a very high ingestion equals CHO oxidation. From this graph rate of oxidation for insoluble starch,[46] this has it can be concluded that oral CHO oxidation may been shown to be due to a methodological error.[38] be optimal at rates of ingestion around 1.0 to 1.5 In conclusion, amylopectin is oxidised at higher g/min. This implies that athletes should ensure a rates than amylose and is therefore a more appro- CHO intake of about 60 to 70g per hour for optimal priate energy source in CHO beverages for athletes. CHO delivery. Adopting an ingestion rate of 60 to Furthermore, insoluble starch may provoke gastro- 70 g/h will optimise exogenous CHO oxidation. intestinal symptoms.[38] 2.3 Multiple Transportable CHOs 2.2.7 Summary The results of various studies are summarised in A study by Shi and colleagues[47] suggested that figure 3. This figure shows the peak oxidation rates, the inclusion of 2 or 3 CHOs (glucose, fructose and which may depend on a variety of factors including sucrose) in a drink may increase water and CHO the exercise intensity, the amount of CHO ingested, absorption despite increased osmolality. This effect and the timing of these feedings. Fructose and ga- was attributed to the separate transport mechanisms lactose appear to be oxidised at relatively low rates, across the intestinal wall for glucose, fructose and whereas glucose, sucrose, maltose, maltodextrins sucrose.[47] Interestingly, fructose absorption from and soluble starch seem to be oxidised at relatively sucrose is also more rapid than the absorption of an

. equimolar amount of fructose. In an elegant study, during 4 hours of exercise at 45% VO2max.This [44] Adopo et al. fed 6 volunteers. CHO at the onset of study suggests that the total amount of CHO seems 2 hours of exercise at 61% VO2max. The CHO feed- to be a more important determinant of exogenous ings were 50g of glucose, 50g of fructose, 100g of CHO oxidation than osmolality or CHO concentra- glucose, 100g of fructose or 50g of glucose plus tion. 50g of fructose. It was found that adding fructose to a glucose solution increases the oral CHO oxi- 2.5 Amount of CHO dation by 21% compared with an iso-energetic glucose solution (fig. 3). The oxidation rate of 50g The amount of CHO that needs to be ingested glucose plus 50g fructose in a combined drink was in order to obtain optimal performance is important higher than the oxidation rate of either 100g glu- from a practical point of view. The optimal amount cose or 100g fructose. However, amounts ingested is likely to be the amount of CHO resulting in max- were relatively small and it remains to be estab- imal exogenous CHO oxidation rates. Pallikarakis [51] lished whether combined ingestion of glucose and et al. found that doubling the amount of CHO fructose can increase exogenous CHO oxidation ingestedfrom200to400gduring285minutesof. more than the ingestion of large amounts of a single exercise at 45% VO2max increased exogenous CHO CHO. Whether addition of galactose to a glucose oxidation. However, exogenous CHO oxidation rates drink can increase total exogenous CHO oxidation did not double and the percentage of the CHO in- in a similar way to glucose and fructose needs to gested that was oxidised was slightly lower (59.5 be determined. and 56.8%, respectively). Here we will refer to this These data suggest that it might be useful to phenomenon as a lower oxidation efficiency with include multiple types of CHO in CHO drinks for thelargerdoseofCHO. athletes. More studies are needed to identify opti- Oxidation efficiency = exogenous CHO mal combinations of different CHOs. oxidation rate/ingestion rate • 100% (Eq. 3)

[31] 2.4 Osmolality and Concentration Rehrer et al. studied the oxidation of different amounts of CHO ingested. during 80 minutes of Gastric emptying and absorption may depend cycling exercise at 70% VO2max. In a randomised on the concentration and osmolality and hence the cross-over design, volunteers received a 4.5% glu- type and amount of CHO, and the volume of the cose solution (a total of 58g glucose during 80 min- ingested beverage. Recent studies seem to suggest utes of exercise) or a 17% glucose solution (220g that CHO content is a more important determinant during 80 minutes of exercise). Exogenous CHO of gastric emptying than osmolality.[48] Therefore, oxidation was measured and these were slightly the CHO type may have little or no effect on the higher with the larger CHO dose (42 and 32g in 80 rate of gastric emptying.[49] It has become clear that minutes, respectively). Thus, even though the am- the CHO type and osmolality of a solution can in- ount of CHO ingested was increased almost 4-fold, fluence intestinal absorption of fluid and CHO. Rel- the oxidation rates were barely affected. The oxi- atively large amounts of glucose in the form of glu- dation efficiency was much lower with the large cose polymers introduced to the gastrointestinal tract amount of CHO (19% for the 17% glucose solution without changing the osmotic load can increase the versus 55% for the 4.5% glucose solution). Inges- glucose delivery and induce greater water absorption of a 17% maltodextrin solution lead to the same tion.[50] Jandrain et al.[19] investigated the oxidation conclusion (i.e. there was a lower oxidation effi- of a 50g glucose load dissolved in either 200, 400 ciency with the more concentrated solution). In a [37] or 600ml of water. Although both the concentration study by Wagenmakers et al., . participants exer- and osmolality were different in these drinks, no dif- cisedfor120minutesat65%VO2max on 5 occa- ferences were observed in exogenous CHO oxidation sions and received 4 doses of maltodextrin ranging

from 72 to 289g. Calculated average ingestion rates CHO as a source of energy. Both an increased mus- were 0.6, 1.2, 1.8 and 2.4 g/min. Although oxida- cle glycogenolysis and increased plasma glucose tion rates increased with increasing intake, exoge- oxidation will contribute to the increased energy nous CHO oxidation seemed to level off after an demands.[52] It is therefore reasonable to suspect intake of 1.2 g/min. Oxidation rates were 0.53, that exogenous CHO oxidation might increase with 0.86, 1.00 and 1.07 g/min, respectively. Also in this increasing exercise intensities. Indeed, an early study study, the oxidation efficiency decreased with in- by Pirnay et al.[53] reported lower exogenous CHO creasing intake (72, 52, 39 and 32%, respectively). oxidation rates at low exercise intensities compared [5] More recently, Jeukendrup et al. investigated with moderate intensities, but exogenous CHO ox- the oxidation rates of even larger CHO intakes on idation tended to level off between 51 and 64% exogenous CHO oxidation. In this study, well trained . VO . In this study, participants exercised for 90 volunteers exercised at a relatively low exercise 2max . minutes on a treadmill on 4 different occasions at intensity of 50% VO for 120 minutes while in- 2max different percentages of their maximal aerobic ca- gesting 70 or 360g of glucose. With the low dose of glucose (average ingestion rate of 0.58 g/min) pacity. They ingested 100g of glucose during exer- exogenous CHO oxidation rates averaged 0.34 cise. The average oxidation rates of the ingested g/min, while with the high dose (average ingestion glucose were 0.18,. 0.36, 0.46 and 0.49 g/min at 22, rate 3.00 g/min) these rates increased up to 0.94 39, 51, and 64% VO2max, respectively. The exoge- g/min. This study also demonstrated a decreased nous CHO oxidation rates did not further increase CHO oxidation efficiency with increasing inges- when the. exercise intensity was increased from 51 tion rates (59 vs 31%). It is interesting to note that to 64% VO2max. although ingestion rates increased up to 2.4 to 3.0 Recently, the same group of researchers found g/min,[5,37] in none of these studies did CHO oxi- an almost similar relationship between the exoge- dation rates exceed 1.1 g/min. nous CHO oxidation rate and the power output on The results of all studies currently available in the a cycle ergometer.[54] The oxidation rate of the in- literature were used to construct figure 3. Although gested CHO increased with. increasing metabolism this graph needs to be interpreted with caution (it for intensities below 60% VO2max. However, when includes studies at different exercise intensities, the. exercise intensity was increased from 60 to 75% different feeding schedules, different volunteer VO2max the oxidation rate leveled off or even de- populations, etc.), it must be concluded that the creased (0.51 and 0.42 g/min, respectively). One maximal rate at which ingested CHO can be oxi- possible explanation for the reduced exogenous oxidised is 1.0 to 1.1 g/min. Increasing the CHO intake dation rate during high exercise intensities (>70 to during exercise may increase oxidation rates until . 75% VO2max) might be the limitation of intestinal the intake exceeds 1.0 to 1.2 g/min. Clearly, the rate digestion and/or absorption, although to our knowl- of oxidation of ingested CHO is limited. However, edge such a limitation has not been shown at exer- the factors limiting exogenous CHO oxidation are . cise intensities below 80% VO . Massicotte et still largely unknown. Possible mechanisms will be 2max al.[28] examined a group of individuals with a wide discussedinsection3. variety of fitness. levels during exercise at 60% of their individual VO . Although volunteers exer- 3. Factors Affecting Exogenous 2max . CHO Oxidation cised at the same relative workload (60% VO2max), there were large differences in the metabolic rate (absolute workload). In agreement with the find- 3.1 Exercise Intensity ings of Pirnay et al.,[53,54] a linear relationship be- With increasing exercise intensity, the exercis- tween the metabolic rate and the oxidation rate of ing muscle becomes more and more dependent on 100g ingested CHO was found.

. However, it could be argued that these findings for 2 hours at 40% VO2max on a cycle ergometer, 1 are an artifact caused by the stable isotopic meth- hour after ingestion of 100g of glucose. The oxida- ods used, rather than a physiological phenomenon. tion rates of the ingested CHOs were similar: 41g As discussed in section 1, some label may be lost in the group with normal glycogen availability and in exchange reactions with the TCA-cycle. It was 38g in the group with reduced glycogen availabil- also shown that at low metabolic rates recovery of ity. However, the study had no cross-over design, the label was only 60 to 70%, whereas at high work which may have influenced the results. Although [13] rates recovery of the label can be 90% or more. the absolute rates of exogenous CHO were not dif- Because no correction was made for label loss in ferent between groups, due to the 20% higher en- the studies cited above, the calculated exogenous ergy expenditure observed in the group of glycogen- CHO oxidation rates could have been underesti- depleted individuals, exogenous CHO oxidation mated, especially at lower metabolic rates. We provided only 16% of the energy yield versus 20% therefore corrected the values for label loss accord- in the group with normal glycogen levels. Thus, the ing to Sidossis et al.[13] However, although the differences were less pronounced after correction, lower glycogen level was associated with a decreased they were still present. Van Loon et al.[55] did not contribution of exogenous CHO oxidation to en- observe differences in exogenous CHO oxidation ergy expenditure during moderate intensity exercise. More recently, Jeukendrup et al.[45] manipulated rates. when trained cyclists exercised at 38 or 55% pre-exercise glycogen levels by glycogen lowering VO2max. It is therefore possible that lower exogenous CHO oxidation rates are only observed at very exercise in combination with CHO restriction (LG low exercise intensities when the reliance on CHO trial) or rest in combination with CHO loading (HG as an energy source is minimal. In this situation, trial). In a randomised cross-over design, volun- part of the ingested CHO may be directed towards teers received an average of 127g. glucose during non-oxidative glucose disposal (storage in the liver 120 minutes of exercise at 57% VO2max.Incontrast or muscle) rather than towards oxidation. Studies to the conclusion of Ravussin et al.,[57] it was found with CHO ingestion during intermittent exercise that exogenous glucose oxidation was 28% lower have suggested that glycogen can be resynthesised in the LG trial compared with the HG trial: 36g of during low intensity exercise.[56] glucose was oxidised during 60 to 120 minutes of It seems fair to conclude. that at exercise inten- exercise during LG, whereas 50g was oxidised with sities below 50 to 60% VO2max, exogenous CHO HG. Péronnet et al.[58] studied the effect of endog- oxidation will increase with increasing total CHO enous CHO availability, after high and low CHO oxidation rates, whereas above approximately 50 . diets, on the oxidation of exogenous. CHOs during to 60% VO2max, oxidation rates will not usually 120 minutes of exercise at 64% VO2max.Volunteers increase further. relied more on exogenous CHO oxidation after the low CHO diet, when glycogen availability was pre- 3.2 Muscle Glycogen sumably low, than after the high CHO diet, when Although determinants of exogenous CHO ox- glycogen availability was presumably high. Between idation have been intensively investigated for al- 40 and 80 minutes of the exercise period, exoge- most 30 years, the effect of pre-exercise glycogen nous CHO oxidation was significantly higher after levels on exogenous CHO oxidation during exer- the low CHO diet compared with the high CHO cise are still largely unknown and studies have pro- diet (0.63 vs 0.52 g/min, respectively). These reduced different results. In a study conducted by sults are inconsistent with the results of Ravussin Ravussin et al.,[57] the oxidation rate of exogenous et al.[57] and Jeukendrup et al.,[45] and are likely glucose was studied in individuals with normal and attributed to differences in experimental conditions low glycogen levels. The 2 groups were observed of exercise and the amounts of CHO ingestion.

Because of the higher relative workload. in the 3.3 Training [58] study of Péronnet et al. (64 vs 40 and 57% VO2max in the studies by Ravussin et al.[57] and Jeukendrup Endurance training has a marked effect on sub- et al.,[45] respectively) and the larger amount of glu- strate utilisation and generally results in a shift from cose ingested (200 vs 100 and 127g in the studies CHO towards fat metabolism. There is a decreased reliance on CHO metabolism after training at the by Ravussin et al.[57] and Jeukendrup et al.,[45] re- same absolute workload.[61-64] However, some con- spectively) volunteers relied more on CHO oxida- troversy still exists regarding whether the reliance tion and less on fat oxidation after both diets. The on CHO as a fuel is also decreased at the same increased reliance on CHO oxidation at this higher relative exercise intensity. Several studies suggest exercise intensity, when glycogen levels are reduced, that even though the exercise after training is per- might explain why exogenous CHO oxidation was formed at the same relative intensity (and thus a higher. higher absolute intensity), there is a decreased re- Another explanation could be that the extent to liance on blood glucose and muscle glycogen.[63-65] which glycogen levels were reduced was responsi- However, some studies did not find a change in ble for the different findings between the studies. glucose uptake after training when compared at the Although none of the above studies measured gly- same relative exercise intensity,[61,62] although [62] cogen levels, the glycogen depletion protocol used plasma glucose oxidation was decreased. Train- in the study by Jeukendrup et al.[45] has previously ing induces several adaptations at the muscular level [66] been shown to result in very low muscle glycogen including an increased GLUT-4content, increased insulin action[67] and an increased capillary bed. levels (<140 mmol/kg dry weight),[59] and to lead All these adaptations would favour glucose uptake to low plasma insulin levels and high plasma free and could possibly alter the handling of blood glu- fatty acids. The 2 to 3 times higher plasma free fatty cose and thus of exogenous glucose. acid level and the lower plasma insulin level when A few studies have investigated the effects of [45,57] glycogen levels were low could have reduced training (or training status) on exogenous CHO ox- [60] plasma glucose uptake and oxidation. Péronnet idation rates.[24,55,68,69] In an early study by Krzen- et al.[58] found a smaller difference in free fatty acid towski et al.,[68] volunteers trained for 6 weeks and levels between their experimental trials, whereas substrate utilisation was measured at the same ab- insulin levels were not different. This was possibly solute exercise intensity before and after the train- due to the moderate glycogen depletion regimen ing programme. The authors concluded that exog- applied in their study, which might therefore ex- enous CHO oxidation was increased by 17% after plain why exogenous CHO oxidation did not de- training. However, the. results seem difficult to increase when glycogen availability was low. terpret. Firstly, the VO2max of the participants was The effect of muscle glycogen on exogenous CHO increased by an unphysiological amount (29%). Sec- oxidation per se is unknown at present. Studies have ondly, in contrast to the literature and despite the improved aerobic capacity after training, no differ- attempted to manipulate muscle glycogen stores by ence in total CHO and fat oxidation was observed. altering the dietary CHO intake and employing ex- More recently, van Loon et al.[55] reported that the ercise programmes but, by doing so, other vari- contribution of CHO to energy expenditure was ables (i.e hormonal changes, high free fatty acid lower in well trained cyclists compared with healthy levels) have been changed as well and these changes untrained controls at the same absolute intensity. may have been responsible for the variable results The reduction in CHO oxidation was due to a re- in different studies. More studies are required to duction in muscle glycogen oxidation (0.10 and 0.75 elucidate the role of muscle glycogen on the oxida- g/min) and endogenous glucose production (0.20 tion rate of ingested CHO. and 0.13 g/min), respectively (fig. 4). However, de-

spite these differences in substrate utilisation, ex- 1.2 Glucose from liver ogenous glucose oxidation rates were unaffected Glucose from feedings 1.0 (0.7 g/min in trained and untrained cyclists). Burelle et al.[24] also compared exogenous CHO 0.8 oxidation in trained and sedentary individuals during exercise at the same absolute workload. Volun- 0.6 teers cycled for 90 minutes at 140W and received 0.4 100g 13C-enriched glucose during exercise. Sur- Ra glucose (g/min) prisingly, no differences were found in total CHO 0.2 and fat oxidation between trained and untrained 0 volunteers. However, although blood glucose oxi- Fast LO-GLU HI-GLU dation rates were not different, exogenous CHO Fig. 4. Glucose delivery to the blood from the liver and gastro- oxidation rates were higher in trained individuals. intestinal tract (feedings) during exercise. During a fast, no glucose feedings were provided and all glucose appearing in the [55] Differences in the results of van Loon et al. and blood stream was derived from the liver. When a small amount Burelle et al.[24] mayalsobecausedbydifferences of glucose was provided (LO-GLU) the total delivery of carbohydrate (CHO) increased but the contribution of liver glucose in the experimental protocol (amount of CHO in- declined. When large amounts of CHO were ingested (HI-GLU), gested, exercise intensity and timing of feedings). the total delivery of CHO was further increased. Liver glucose For instance, Burelle et al.[24] gave their first feed- output was negligible and all glucose was derived from the feedings. Ra = rate of appearance (adapted from Jeukendrup et ing (25g glucose) 30 minutes before exercise, which al.,[70] with permission). means that glycogen stores may have been pre-labeled, particularly in the trained volunteers who are more insulin sensitive and will have an increased creased muscle glycogen use, which is in contrast muscle glucose uptake after an oral glucose load. with most of the literature showing either no change This would result in an overestimation of exoge- or a decreased intramuscular glycogen breakdown nous CHO oxidation rates during exercise in the after training at the same relative intensity.[61,62] trained volunteers. If trained individuals stored 20% In section 4 of this review we will discuss how more of the initial glucose gift (5g) than the un- maximal exogenous CHO oxidation rates are reg- trained individuals, this could explain the entire ulated. This concept, which is based on the premise observed difference in exogenous CHO oxidation. that the liver and intestine play a crucial role in This seems a reasonable assumption since it has glucose homeostasis, describes that a maximal glu- been shown that post-exercise, glycogen resynthe- cose output by the liver controls maximal exogenous sis can be twice as fast after endurance training.[71] CHO oxidation rates. This concept would predict that Three studies have investigated the effects of exogenous CHO oxidation rates are similar in trained exogenous CHO oxidation during exercise at the and untrained individuals at the same absolute and same relative exercise intensity.[24,55,69] Two stud- relative workload. Higher exogenous CHO oxida- ies showed no effect of training on the oxidation of tion rates in trained individuals would suggest a superior absorption or more exogenous glucose ingested CHO, whereas Burelle et al.[24] reported would escape from the liver. There are currently no higher oxidation rates in trained compared with un- . data available to support these potential differences trained individuals at 68% VO . 2max between trained and untrained individuals. The difference between these studies may be related to the fact that the latter study showed an 4. Limitations of Exogenous increase in total CHO oxidation in trained individ- CHO Oxidation uals, whereas no changes in CHO oxidation were found in the studies by van Loon et al.[55] and Jeu- As depicted in figure 3, exogenous CHO oxida- kendrup et al.[69] Burelle et al.[24] also reported in- tion seems to be limited to rates of 1.0 to 1.1 g/min.

[27,38] CHO and feeding schedules. Because in these studies ingestion rate only 32 to 48% of the CHO delivered to the intes- Gastrointestinal tract >2.0 g/min tine was oxidised, it was concluded that gastric emptying was not limiting exogenous CHO oxidation. ? g/min Glucogen Another potential rate-limiting factor is intesti- 1.2-1.7 g/min Liver nal absorption of CHO. Studies using a triple lu- 1.0 g/min 0-1.0 g/min men technique have measured duodenojejunal glucose absorption and estimated whole body intestinal 1.0 g/min absorption rates of a 6% glucose-electrolyte solution.[72] It was estimated that the maximal absorp- Glucose Blood tion rate of the intestine ranged from 1.3 to 1.7 1.0 g/min g/min. Recent studies using stable isotope method- Muscle ology have tried to quantify the appearance of glucose from the gut into the systemic circulation (Ra 1.0 g/min gut). When a low dose of CHO was ingested during exercise, the rate of appearance of glucose from the CO 2 gut equaled the rate of CHO ingestion during the Fig. 5. Regulation of hepatic glucose production and the control [5] of glucose appearance into the systemic circulation with carbo- second hour (both 0.43 g/min). This implies that hydrate (CHO) ingestion. CHO can be ingested at fairly high at low ingestion rates absorption is not limiting and rates up to about 3 g/min before causing gastrointestinal symp- there is no net storage of glucose in the liver. In- toms. This CHO will then be digested and absorbed at a rate of 1.2to1.7g/min,whichhasbeensuggestedtobethemaximal stead, all ingested glucose appears in the blood absorptive capacity of the intestine. CHO will then enter the liver stream. It was also found that the glucose appearing through the portal vein. A maximum of 1 g/min will escape from in the bloodstream was taken up at similar rates to the liver and enter the bloodstream. The CHO entering the bloodstream may be derived from ingested CHO (in extreme its Ra and 90 to 95% of this glucose was oxidised conditions1g/min),canbederivedfromtheliver(glycogenoly- during exercise. When a larger dose of CHO was sis and gluconeogenesis) at a rate of 0 to 1 g/min, or can be ingested (3 g/min), Ra gut was one-third the rate of derived from a combination of both. Whether glucose from ingested CHO can be directed towards liver glycogen during ex- CHO ingestion (0.96 to 1.04 g/min). Thus, only ercise has not been established. Glucose will be taken up by part of the ingested CHO entered the systemic cir- the muscle and can be oxidised at virtually similar rates. This graph was composed with results from various studies.[5,8,72] culation. However, the glucose appearing in the blood was taken up and 90 to 95% was oxidised. It was therefore concluded that entrance into the systemic This finding seems supported by the vast majority circulation is a limiting factor for exogenous glu- of studies using either radioactive[3,36] or sta- cose oxidation, rather than intramuscular factors. ble[5,37,45,53,69] isotopes to quantify exogenous CHO This is further supported by glucose infusion stud- oxidation during exercise. One of the limiting fac- ies. Hawley et al.[73] bypassed both intestinal ab- tors could be gastric emptying. However, Rehrer et sorption and hepatic glucose uptake by infusing. [31] al. showed that gastric emptying is unlikely to glucose in volunteers exercising at 70% VO2max. affect exogenous CHO oxidation rates. In their study, When large amounts of glucose were infused and participants ingested 220g. glucose during 80 min- volunteers were hyperglycemic (10 mmol/L), it was utes of exercise at 70% VO2max.After80minutes, possible to raise blood glucose oxidation rates above 100g of glucose was present in the stomach and 1 g/min. thus 120g was delivered to the duodenum. How- These studies provide evidence that exogenous ever, at 80 minutes only 38g of the ingested CHO CHO oxidation is limited by the rate of digestion, was oxidised. These results were later confirmed absorption and subsequent transport of glucose into by others using slightly different exercise protocols the systemic circulation rather than the rate of up-

take and oxidation by the muscle. The maximal Fat rates of intestinal absorption seem to be slightly in Muscle glycogen Hepatic glucose output excess of the maximal appearance of glucose from 3 Exogenous carbohydrate the gut into the bloodstream.[5] It is important to note that during high intensity exercise, a reduced mesenteric blood flow may result in a decreased * 2 absorption of glucose and water[50] and hence a low * Ra gut relative to the rate of ingestion. However, this may only apply to exercise at very high inten- * sities.[50] Taken together, this suggests that intesti- 1 nal absorption is a factor contributing to the limi- * tation to oxidise ingested CHO at rates higher than utilisation (g/min) Substrate

1.0to1.1g/min,butitmaynotbethesolefactor. 0 The liver may play an additional important role. T1 UT T2 Hepatic glucose output is highly regulated and it is Fig. 6. Substrate utilisation in untrained (UT) and trained indi- possible that the glucose output derived from the viduals at the same absolute (T1) and relative exercise intensity intestine and from hepatic glycogenolysis and glu- (T2). UT and T1. is exercise at 148W [55 and 38% maximal oxygen. uptake (VO2max), respectively] and T2 is exercise at 200W coneogenesis will not exceed 1.0 to 1.1 g/min even (55% VO2max). though the absorption is slightly in excess of this rate (fig. 5). If supply from the intestine is too large very high rates, may not enter the systemic circu- (>1.0 g/min), glycogenesis may be activated in the lation at these high rates. The relative role of ab- liver. Recent findings by Jeukendrup et al.[5] support sorption and the liver retaining glucose remain to the role of the liver. Ingestion of small CHO doses be determined. With the recent developments in during exercise suppressed endogenous (mainly nuclear magnetic resonance spectroscopy it should liver) glucose production (fig. 6). Very high rates be possible to more accurately determine the role of CHO intake (3 g/min) completely suppressed en- [78] dogenous glucose production. However, despite of the liver. these high rates of ingestion the total Ra did not Another question, which may be beyond the scope exceed 1 g/min. Assuming that CHO was absorbed of this review, is related to the performance effects at a rate slightly in excess of 1 g/min, this would of glucose feedings during exercise. It has been suggest glycogenesis in the liver during exercise. shown that CHO feeding during exercise can im- The hormonal profile as observed after ingesting prove performance when the exercise duration is [1,79,80] large amounts of glucose during exercise (higher only about 60 minutes. It was calculated that plasma insulin and lower plasma glucagon levels) by this time only 5 to 15g of the ingested glucose [1] would support glycogenesis by activating hepatic could have been oxidised, and it is therefore un- glycogen synthase activity,[74] GLUT-2 transporter likely that this small contribution causes the rela- expression,[75] increased glucose kinase expres- tively large effect on performance. However, alter- sion[76] or liver cell swelling.[77] native mechanisms are currently unknown. Other questions, which may have important practical im- 5. Directions for Future Research plications, are related to exercise in extreme conditions (heat, altitude). Formulated guidelines are Although many advances have been made in the primarily based on studies in thermoneutral and last few years, several questions remain to be an- sea level conditions. swered. One of the intriguing questions is the fate However, it is possible that these guidelines are of excess amounts of ingested CHO. Recent stud- not suitable for exercise in the heat or at high alti- ies have revealed that glucose, when ingested at tude. Both conditions have been shown to result in

marked changes in substrate utilisation at rest and Acknowledgements during exercise.[81,82] Prolonged exercise in the heat will lead to distribution of blood to the skin to allow The authors want to acknowledge the invaluable support from and fruitful discussions with Dr Anton Wagenmakers, [83] for evaporative cooling. As a consequence, blood Professor Wim Saris and Dr Fred Brouns at Maastricht flow to other organs such as the liver, kidney, inac- University in The Netherlands. We also want to thank Pro- tive tissue and the gut will be reduced.[84,85] Are- fessor Mike Gleeson for his careful and critical reviewing of duced blood flow to the gut may impair gut func- this manuscript. tion, especially during ultra-endurance exercise, as recently suggested.[70] Absorption of CHO (and other References 1. Jeukendrup AE, Brouns F,Wagenmakers AJM,et al.Carbohydrate nutrients) may be impaired, which may finally lead feedings improve 1 h time trial cycling performance. Int J to a reduced oxidation rate of ingested CHO. This Sports Med 1997; 18: 125-9 may also partly explain why CHO feeding during 2. Coyle EF, Coggan AR, Hemmert MK, et al. Muscle glycogen utilization during prolonged strenuous exercise when fed car- exercise in the heat has no effect on endurance per- bohydrate. J Appl Physiol 1986; 61: 165-72 formance.[86-88] Future studies are therefore needed 3. Bosch AN, Dennis SC, Noakes TD. Influence of carbohydrate ingestion on fuel substrate turnover and oxidation during pro- to investigate the effect of heat on exogenous CHO longed exercise. J Appl Physiol 1994; 76: 2364-72 oxidation during exercise to prevent needless in- 4. McConnell G, Fabris S, Proietto J, et al. Effect of carbohydrate ingestion on glucose kinetics during exercise. J Appl Physiol take of excess CHO, which can not be absorbed and 1994; 77 (3): 1537-41 functions as a potential risk factor for gastrointes- 5. Jeukendrup AE, Wagenmakers AJ, Stegen JH, et al. Carbohydrate tinal problems. ingestion can completely suppress endogenous glucose production during exercise. Am J Physiol 1999; 276: E672-83 6. Tsintzas OK, Williams C, Boobis L, et al. Carbohydrate ingestion 6. Practical Implications, Guidelines and single muscle fiber glycogen metabolism during prolonged running in men. J Appl Physiol 1996; 81: 801-9 and Conclusion 7. Tsintzas OK, Williams C, Boobis L, et al. Carbohydrate ingestion and glycogen utilisation in different muscle fibre types in man. The above findings have some practical appli- J Physiol 1995; 489: 243-50 cations, some of which are summarised here: 8. Jeukendrup AE, Raben A, Gijsen A, et al. Glucose kinetics during prolonged exercise in highly trained human subjects: effect of • Athletes should ensure a CHO intake of approx- glucose ingestion. J Physiol (Lond) 1999; 515: 579-89 imately1.0to1.1g/min(60to70g/h). 9. Tsintzas K, Williams C. Human muscle glycogen metabolism • during exercise: effect of carbohydrate supplementation. Sports The bulk of ingested CHO should be a rapidly Med 1998; 25: 7-23 oxidisable CHO: glucose, maltose, sucrose, 10. Costill DL, Bennett A, Branam G, et al. Glucose ingestion at maltodextrins or amylopectin (soluble starch). rest and during prolonged exercise. J Appl Physiol 1973; 34: 764-9 • Small amounts of fructose or sucrose may be 11. Beckers EJ, Halliday D, Wagenmakers AJ. Glucose metabolism added to a glucose or maltodextrin solution (up and radioactive labeling: what are the real dangers? Med Sci Sports Exerc 1994; 26: 1316-8 to 20% of the total CHO content may be fruc- 12. Robert JJ, Koziet J, Chauvet D, et al. Use of 13C-labeled glucose tose). for estimating glucose oxidation: some design considerations. • J Appl Physiol 1987; 63: 1725-32 Untrained individuals may benefit as much as 13. Sidossis LS, Coggan AR, Gastaldelli A, et al. A new correction trained athletes since exogenous CHO oxidation factor for use in tracer estimations of plasma fatty acid oxidation. rates and effects on performance appear to be Am J Physiol 1995; 269: E649-56 14. Jeukendrup AE, Wagenmakers AJM, Brouns F, et al. Effects of similar. carbohydrate (CHO) and fat supplementation on CHO meta- Based on a relatively large number of studies, bolism during prolonged exercise. Metabolism 1996; 45: 915-21 15. Sidossis LS, Coggan AR, Gastadelli A, et al. Pathways of free guidelines for CHO feeding during exercise are now fatty acid oxidation in human subjects: implications for tracer quite detailed. However, future research should elu- studies. J Clin Invest 1995; 95: 278-84 cidate whether these guidelines apply to all condi- 16. Schrauwen P, van Aggel-Leijssen DP, van Marken Lichtenbelt WD, et al. Validation of the [1,2-13C]acetate recovery factor tions (altitude, heat, cold) and whether combination for correction of [U-13C]palmitate oxidation rates in humans. of different CHO can lead to exogenous CHO ox- J Physiol (Lond) 1998; 513: 215-23 17. Péronnet F, Massicotte D, Brisson G, et al. Use of 13Csubstrates idation rates higher than 1 g/min. If this is the case, for metabolic studies in exercise: methodological considera- guidelines may have to be adjusted accordingly. tions. J Appl Physiol 1990; 69: 1047-52

13 18. Wagenmakers AJM, Rehrer NJ, Brouns F, et al. Breath CO2 39. Okano G, Takeda H, Morita I, et al. Effect of pre-exercise fructose background enrichment at rest and during exercise: diet re- ingestion on endurance performance in fed man. Med Sci lated differences between Europe and America. J Appl Physiol Sports Exerc 1988; 20: 105-9 1993; 74: 2353-7 40. Koivisto VA, Karonen S-L, Nikkila EA. Carbohydrate ingestion 19. Jandrain BJ, Pirnay F, LaCroix M, et al. Effect of osmolality on before exercise: comparison of glucose, fructose and placebo. availability of glucose ingested during prolonged exercise in J Appl Physiol 1981; 51: 783-7 humans. J Appl Physiol 1989; 67: 76-82 41. Samols E, Dormandy TL. Insulin response to fructose and ga- 20. Krzentowski G, Jandrain B, Pirnay F, et al. Availability of glucose lactose. Lancet 1963; I: 478-9 given orally during exercise. J Appl Physiol 1984; 56: 315-20 42. Jandrain BJ, Pallikarakis N, Normand S, et al. Fructose utilization 21. Pirnay F, Lacroix M, Mosora F, et al. Effect of glucose ingestion during exercise in men: rapid conversion of ingested fructose on energy substrate utilization during prolonged exercise in to circulating glucose. J Appl Physiol 1993; 74: 2146-54 man. Eur J Appl Physiol 1977; 36: 1620-4 43. Burelle Y, Péronnet F, Massicotte D, et al. Oxidation of 13C- 22. Pirnay F, Lacroix M, Mosora F, et al. Glucose oxidation during glucose and 13C-fructose ingested as a preexercise meal: effect prolonged exercise evaluated with naturally labelled [13C] glu- of carbohydrate ingestion during exercise. Int J Sport Nutr cose. J Appl Physiol 1977; 43: 258-61 1997; 7: 117-27 23. Guezennec CY, Satabin P, Duforez F, et al. Oxidation of corn 44. Adopo E, Péronnet F, Massicotte D, et al. Respective oxidation starch, glucose, and fructose ingested before exercise. Med of exogenous glucose and fructose given in the same drink Sci Sports Exerc 1989; 21: 45-50 during exercise. J Appl Physiol 1994; 76: 1014-9 24. Burelle Y, Péronnet F, Charpentier S, et al. Oxidation of an oral 45. Jeukendrup AE, Borghouts L, Saris WHM, et al. Reduced oxi- [13C]glucose load at rest and prolonged exercise in trained dation rates of orally ingested glucose during exercise after and sedentary subjects. J Appl Physiol 1999; 86: 52-60 low CHO intake and low muscle glycogen. J Appl Physiol 25. Massicotte D, Péronnet F, Brisson G, et al. Oxidation of exoge- 1996; 81: 1952-7 nous carbohydrate during prolonged exercise in fed and fasted 46. Hawley JA, Dennis SC, Laidler BJ, et al. High rates of exogenous conditions. Int J Sports Med 1990; 11: 253-8 carbohydrate oxidation from starch ingested during prolonged 26. Massicotte D, Péronnet F, Brisson G, et al. Oxidation of a glucose exercise. J Appl Physiol 1991; 71: 1801-6 polymer during exercise: comparison with glucose and fruc- 47. Shi X, Summers R, Schedl H, et al. Effects of carbohydrate type tose. J Appl Physiol 1989; 66: 179-83 and concentration and solution osmolality on water absorption. 27. Moodley D, Noakes TD, Bosch AN, et al. Oxidation of exogenous Med Sci Sports Exerc 1995; 27: 1607-15 carbohydrate during prolonged exercise: the effects of the 48. Brouns F, Senden J, Beckers EJ, et al. Osmolarity does not carbohydrate type and its concentration. Eur J Appl Physiol affect the gastric emptying rate of oral rehydration solutions. 1992; 64: 328-34 J Parent Enter Nutr 1995; 19: 403-6 28. Massicotte D, Péronnet F, Adopo E, et al. Effect of metabolic 49. Shi X, Gisolfi CV. Fluid and carbohydrate replacement during rate on the oxidation of ingested glucose and fructose during intermittent exercise. Sports Med 1998; 25: 157-72 exercise. Int J Sports Med 1994; 15: 177-80 50. Brouns F, Beckers E. Is the gut an athletic organ? Digestion, 29. Rehrer NJ, Brouns F, Beckers EJ, et al. Gastric emptying with absorption and exercise. Sports Med 1993; 15: 242-57 repeated drinking during running and bicycling. Int J Sports Med 1990; 11: 238-43 51. Pallikarakis N, Jandrain B, Pirnay F, et al. Remarkable metabolic 30. Noakes TD, Rehrer NJ, Maughan RJ. The importance of volume availability of oral glucose during long-duration exercise in in regulating gastric emptying. Med Sci Sports Exerc 1991; humans. J Appl Physiol 1986; 60: 1035-42 23: 307-13 52. Romijn JA, Coyle EF, Sidossis LS, et al. Regulation of endog- 31. Rehrer NJ, Wagenmakers AJM, Beckers EJ, et al. Gastric emp- enous fat and carbohydrate metabolism in relation to exercise tying, absorption and carbohydrate oxidation during prolonged intensity. Am J Physiol 1993; 265: E380-91 exercise. J Appl Physiol 1992; 72: 468-75 53. Pirnay F, Crielaard JM, Pallikarakis N, et al. Fate of exogenous 32. McConell G, Kloot K, Hargreaves M. Effect of timing of carbo- glucose during exercise of different intensities in humans. J hydrate ingestion on endurance exercise performance. Med Appl Physiol 1982; 53: 1620-4 Sci Sports Exerc 1996; 28 (10): 1300-4 54. Pirnay F, Scheen AJ, Gautier JF, et al. Exogenous glucose oxi- 33. Massicotte D, Péronnet F, Allah C, et al. Metabolic response to dation during exercise in relation to the power output. Int J [13C] glucose and [13C] fructose ingestion during exercise. J Sports Med 1995; 16: 456-60 Appl Physiol 1986; 61: 1180-4 55. van Loon LJ, Jeukendrup AE, Saris WH, et al. Effect of training 34. Décombaz J, Sartori D, Arnaud M-J, et al. Oxidation and meta- status on fuel selection during submaximal exercise with glu- bolic effects of fructose and glucose ingested before exercise. cose ingestion. J Appl Physiol 1999; 87: 1413-20 Int J Sports Med 1985; 6: 282-6 56. Kuipers H, Saris WHM, Brouns F, et al. Glycogen synthesis 35. Leijssen DPC, Saris WHM, Jeukendrup AE, et al. Oxidation of during exercise and rest with carbohydrate feeding in males orally ingested [13C]-glucose and [13C]-galactose during ex- and females. Int J Sports Med 1989; 10: S63-7 ercise. J Appl Physiol 1995; 79: 720-5 57. Ravussin E, Pahud P, Dorner A, et al. Substrate utilization during 36. Hawley JA, Dennis SC, Nowitz A, et al. Exogenous carbohydrate prolonged exercise preceded by ingestion of 13C-glucose in oxidation from maltose and glucose ingested during prolonged glycogen depleted and control subjects. Pflügers Arch 1979; exercise. Eur J Appl Physiol 1992; 64: 523-7 382: 197-202 37. Wagenmakers AJM, Brouns F, Saris WHM, et al. Oxidation 58. Péronnet F, Rheaume N, Lavoie C, et al. Oral [13C]glucose rates of orally ingested carbohydrates during prolonged exercise oxidation during prolonged exercise after high- and low-carbo- in man. J Appl Physiol 1993; 75: 2774-80 hydrate diets. J Appl Physiol 1998; 85 (2): 723-30 38. Saris WHM, Goodpaster BH, Jeukendrup AE, et al. Exogenous 59. Kuipers H, Keizer HA, Brouns F, et al. Carbohydrate feeding carbohydrate oxidation from different carbohydrate sources and glycogen synthesis during exercise in man. Pflügers Arch during exercise. J Appl Physiol 1993; 75: 2168-72 1987; 410: 652-6

60. Hargreaves M, Kiens B, Richter EA. Effect of increased plasma 76. Iynedjian PB, Gjinovci A, Renold AE. Stimulation by insulin of free fatty acid concentrations on muscle metabolism in exer- glucokinase gene transcription in liver of diabetic rats. J Biol cising men. J Appl Physiol 1991; 70: 194-201 Chem 1988; 263: 740-4 61. Bergman BC, Butterfield GE, Wolfel EE, et al. Muscle net glucose 77. Al-Habori M, Peak M, Thomas TH, et al. The role of cell swelling uptake and glucose kinetics after endurance training in men. in the stimulation of glycogen synthesis by insulin. Biochem Am J Physiol 1999; 277: E81-92 J 1992; 282: 789-96 62. Friedlander AL, Casazza GA, Horning MA, et al.Training induced 78. Casey A, Mann R, Banister K, et al. Effect of carbohydrate alterations of glucose flux in men. J Appl Physiol 1997; 82: ingestion on glycogen resynthesis in human liver and skeletal 1360-9 muscle, measured by (13)C MRS. Am J Physiol Endocrinol 63. Coggan AR, Kohrt WM, Spina RJ, et al. Plasma glucose kinetics Metab 2000; 278 (1): E65-75 during exercise in subjects with high and low lactate thresholds. 79. Anantaraman R, Carmines AA, Gaesser GA, et al. Effects of J Appl Physiol 1992; 73: 1873-80 carbohydratesupplementationonperformanceduring1hof 64. Coggan AR, Raguso CA, Williams BD, et al. Glucose kinetics high intensity exercise. Int J Sports Med 1995; 16: 461-5 during high-intensity exercise in endurance-trained and un- 80. Below PR, Mora-Rodríguez R, Gonzáles Alonso J, et al. Fluid trained humans. J Appl Physiol 1995; 78: 1203-7 and carbohydrate ingestion independently improve performance 65. Jansson E, Kaijser L. Substrate utilization and enzymes in skeletal during 1 h of intense exercise. Med Sci Sports Exerc 1995; muscle of extremely endurance-trained men. J Appl Physiol 27: 200-10 1987; 62: 999-1005 81. Febbraio MA, Snow RJ, Hargreaves M, et al. Muscle metabolism 66. Richter EA, Kiens B, Saltin B, et al. Skeletal muscle glucose uptake during dynamic exercise in humans: role of muscle during exercise and heat stress in trained men: effect of accli- mass. Am J Physiol 1988; 254: E555-61 mation. J Appl Physiol 1994; 76: 589-97 67. Dela F, Mikines KJ, von Linstow M, et al. Effect of training on 82. Hargreaves M, Angus D, Howlett K, et al. Effect of heat stress insulin-mediated glucose uptake in human muscle. Am J Physiol on glucose kinetics during exercise. J Appl Physiol 1996; 81: 1992; 263: E1134-43 1594-7 68. Krzentowski GB, Pirnay F, Luyckx AS, et al. Effect of physical 83. Johnson JM, Park MK. Reflex control of skin blood flow by training on utilization of a glucose load given orally during skin temperature: role of core temperature. J Appl Physiol exercise. Am J Physiol 1984; 246: E412-7 1979; 47: 1188-93 69. Jeukendrup AE, Mensink M, Saris WHM, et al. Exogenous glu- 84. Williams JH, Mager M, Jacobson ED. Relationship of mesenteric cose oxidation during exercise in endurance-trained and un- blood flow to intestinal absorption of carbohydrates. J Lab trained subjects. J Appl Physiol 1997; 82: 835-40 Clin Med 1964; 63: 853-63 70. Jeukendrup AE, Vet-Joop K, Sturk A, et al. Relationship between 85. Clausen JP.Effect of physical training on cardiovascular adjust- gastro-intestinal complaints and endotoxaemia, cytokine re- ments to exercise in man. Physiol Rev 1977; 57: 779-815 lease and the acute-phase reaction during and after a long- 86. Febbraio M, Murton P, Selig S, et al. Effect of CHO ingestion distance triathlon in highly trained men. Clin Sci (Colch) 2000; on exercise metabolism and performance in different ambient 98: 47-55 temperatures. Med Sci Sports Exerc 1996; 28: 1380-7 71. Greiwe JS, Hickner RC, Hansen PA, et al. Effects of endurance 87. Davis JM, Lamb DR, Pate RR, et al. Carbohydrate-electrolyte exercise training on muscle glycogen accumulation in humans. drinks: effects on endurance cycling in the heat. Am J Clin J Appl Physiol 1999; 87: 222-6 Nutr 1988; 48: 1023-30 72. Duchman SM, Ryan AJ, Schedl HP,et al. Upper limit for intestinal 88. Millard-Stafford M, Sparling PB, Rosskopf LB, et al. Carbohy- absorption of a dilute glucose solution in men at rest. Med Sci drate-electrolyte replacement during a simulated triathlon in Sports Exerc 1997; 29: 482-8 the heat. Med Sci Sports Exerc 1990; 22: 621-8 73. Hawley JA, Bosch AN, Weltan SM, et al. Glucose kinetics during prolonged exercise in euglycemic and hyperglycemic subjects. Pflügers Arch 1994; 426: 378-86 74. Mandarino LJ, Consoli A, Jain A, et al. Differential regulation Correspondence and offprints: Dr Asker E. Jeukendrup, Hu- of intracellular glucose metabolism by glucose and insulin in man Performance Laboratory, School of Sport and Exercise human muscle. Am J Physiol 1993; 265: E898-905 75. Postic C, Burcelin R, Rencurel F, et al. Evidence for a transient Sciences, University of Birmingham, Edgbaston, Birming- inhibitory effect of insulin on GLUT2 expression in the liver: ham B15 2TT, England. studies in vivo and in vitro. Biochem J 1993; 293: 119-24 E-mail: [email protected]