carbohydrate ingestion can completely suppress endogenous glucose production during exercise

7/28/2019 Carbohydrate Ingestion Can Completely Suppress Endogenous Glucose Production During Exercise

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276:672-683, 1999.Am J Physiol Endocrinol MetabGijsen, Fred Brouns and Wim H.M. SarisAsker E. Jeukendrup, Anton J.M. Wagenmakers, Jos H.C.H. Stegen, Annemie P.

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Ca rbohydr a t e ingestion ca n complet ely suppress

endogenous glucose production during exercise

AS K E R E. J EU K EN D RUP, AN TON J . M . WAG EN M AK ERS , J OS H. C. H. S TEG EN ,

A N N EM I E P. G I J S EN , F RED B ROUN S , A N D WI M H. M . S A RI S

Departm ent of H um an Bi ology, N utr i t ion Research Centr e,

M a a str i ch t U n i ver s i ty, 6 2 00 M D M a a str i ch t , T h e N eth er l a n d s

J eukendrup,Asker E.,AntonJ .M.Wagenmakers,J osH. C. H. Stegen, Annemie P. Gijsen, Fred Brouns, andWim H. M. Saris. Ca rbohydra t e ingest ion ca n complet elysuppress endogenous glucose production dur ing exercise. Am .J. Physiol. 276 (End ocri nol. Metab. 39): E672E683, 1999.The purposes of this st udy were 1) to investigat e the effect ofcarbohydra te (CHO) ingestion on endogenous glucose produc-tion (EGP) during prolonged exercise, 2) t o s t u d y w h e t h erglucose a ppea ra n ce in t he circula t ion could be a l imit ingfa ct or for exogenous CHO oxida t ion, a nd 3) t o inves t iga t ew het her la rge C HO feedings ca n reduce mus cle glycogenoxidation during exercise. Six well-trained subjects exercisedt hree t imes for 120 min a t 50% ma ximum w orkloa d w hileingesting water (FAST), a 4%glucose solution (LO-Glc), or a22%glucose solution (HI-Glc). A primed continuous intrave-nous [6,6-2H 2]glucos e infus ion w a s given, a nd t he inges t edglucose was enriched with [U-13C]glucose. Glucose ingestions ignifica nt ly eleva t ed CHO oxida t ion a s w ell a s t he ra t es ofappearance (R a ) a nd dis a ppea ra n ce. R a glucose equa led R a ofglucose in gut (R a g u t ) d ur i n g H I -G l c , w h e r ea s E G P w a scomplet ely s uppres s ed. D uring L O-G lc, E GP w a s pa rt ia l lysuppressed, wherea s R a gut provided most of the total glucoseR a . We conclude t ha t 1) h i g h r a t e s o f C H O i n g e s t i o n c a ncompletely block EG P, 2) R a gut ma y be a l imit ing fa ct or forexogenous CHO oxidation, and 3) muscle glycogen oxidationwa s not reduced by large glucose feedings.

stable isotopes; glucose kinetics; glycogen; endogenous glu-cose output; glucose metabolism; sport nutrition

B L O O D G L U C O S E is an im porta n t su b strat e d u rin g exer-cise. Whole body glucose turnover is enhanced duringexercise because of increases in muscle glucose uptakeand endogenous glucose production (EGP, i.e., in liveran d k idn e y) (5). Re gu lat io n o f E G P is com p le x a n din volves b oth fee d forwa rd (m e d iat e d b y th e cen tra lnervous system) and feedback mechanisms (responseto decreas ed plas ma glucose levels) (for review see Ref.55). I ncreased glucose upta ke during exercise ma y becau sed b y act ivat io n o f p at h wa ys re spon sible for g lu -cose disposal, increased capillary blood flow, and in-

cr ea s e d m em b r a n e g lu cos e t r a n s p or t i n t h e a c t i vem u scle . I n p re vio u s stu d ie s, m ak in g u se o f th e h ig hn a t u r a l 13C a b u n d a n ce of ca r b oh y d r a t e s (C H O ), w eh ave sh o wn th at CHO in g e stio n d u rin g e xe rcise re -duces the oxidation of endogenous CHO (28, 30). Inthese studies, however, it was not possible to investi-g ate wh e th e r m u scle g lyco g e n o xid atio n o r th e EG P

wa s reduced. Therefore, the fi rst purpose of this st udyw a s t o e x a m i n e t h e e f f e c t o f s m a l l a n d l a r g e C H Ofeedings during exercise on E G P.

Th e sou rce of th e b lood g lu cose oxidiz ed d u rin gex er ci se m a y b e f r om t h e l iv er , o r, w h e n C H O a r eingested, glucose may be absorbed from the gast rointes-tina l syst em. The oxidat ion of ingested CHO ha s beenintensively investigat ed w ith sta ble-isotope techniquesinvolving the ingestion of naturally labeled [13C]glucose(32, 33, 38, 43, 54). Fr om th ese studies, it a ppears th a texogenous CHO oxidation is limited to 1 g /mi n (22,54). Even ingestion rates 2 g/min did not result in

o xid atio n rate s 1 g/min (54). Rehrer et a l. (43) in-crea sed the ra te of CHO ingestion fourfold, but t he ra teo f o xid atio n in cre ase d o n ly two fo ld . T h e fate o f th ere m ain in g CHO w as n ot id en tifi e d . I t h as b ee n sh ownt h a t m o s t o f t h e i n g e s t e d C H O i s e m p t i e d f r o m t h es t o m a c h a n d t h a t g a s t r i c e m p t y i n g i s n o t t h e r a t e -limiting step for exogenous CHO oxidation (43). I t ispossible that part of the ingested CHO still remains inth e intest ines or tha t it is stored in tissues like liver andinactive muscles. Therefore, a second purpose of t hiss t u d y w a s t o i n v es t i ga t e w h e t h er t h e r a t e o f a p pe a r -an ce (R a ) of glucose into the systemic circulation is alimiting fa ctor of exogenous CH O oxida tion.

Although ma ny studies ha ve shown th a t th e ingestion

of CHO during prolonged exercise enhances enduranceperformance (5, 6, 10), the underlying mechanisms arestill incompletely understood. The experimental evi-dence collected during the past 15 years suggests twopossible physiological-meta bolic mecha nisms th a t couldbe responsible for t he ergogenic effect of CH O ingest ionduring prolonged subma xima l exercise. The fi rst mech-an ism explains t he improved performance by the ma in-tenance of high blood glucose levels, especially late inexercise when the muscle glycogen concentr a tions a rereduced. The second m echa nism could be a reducedra te of muscle glycogen ut ilizat ion, w hich would delayth e depletion of the glycogen st ores an d hence the onsetof fatigue.

Evidence for t he fir st m echa nism stems from a seriesof studies by Coyle and colleagues (6, 10), who observedth a t g lycog e n b reak d o wn w as n ot re d u ce d wh e n CH Owere ingested during cycling exercise at 70%ma ximalO2 consum ption (VO2 m a x). I n s t ea d , d u r in g t h e l a t e rsta ges of exercise, CHO ing estion prevented hypoglyce-m ia an d im proved e xe rcise p erform a n ce m a rk ed ly.These authors therefore concluded that CHO ingestionduring exercise maintains blood glucose levels in theeu g ly ce mi c r a n g e a n d en s u r es h i gh C H O ox id a t i onrates during the late phase of exercise when glycogensto res ar e n e arly d e plete d . Th e se fi n d in gs h ave b ee n

The costs of publication of this article were defrayed in part by thep a y m e n t of p a g e c h a r g es . Th e a r t ic le m u s t t h e r ef or e b e h e r e bymarked advertisement in accordan ce with 18 U.S.C. Sect ion 1734solely to indicate this fact.

0193-1849/99 $5.00 Cop yr igh t 1999 the American Physiological SocietyE672


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con fi rm e d b y se ve ral oth e r re sear che rs. I n con tra stwith th e se fi n d in g s, oth e r stu d ie s su gg e ste d th a t CHOingestion ma y improve endura nce performa nce by slow-ing the rate of muscle glycogen degradation (2, 19, 52,53). For example, Tsintza s a nd collea gues (52, 53)showed tha t net muscle glycogen brea kdown a fter CH Oin g estion d u rin g ru n n in g a t 70% VO2 m a x wa s re d u ce d ,a nd t his glycogen spa ringoccurr ed alm ost exclusivelyin ty pe I muscle fibers.

Severa l explana tions ha ve been given for th ese a ppar-ently contradictory findings. There may be fundamen-ta l d i f fe ren ces in m e tab o lism b e twe e n r u n n in g a n dcycling (51). Second, caution must be exercised whendra wing conclusions a bout muscle glycogen ut iliza tionfrom the analysis of glycogen concentrations in localmixed muscle samples in studies involving CHO inges-tion a nd prolonged exercise (51). Afa irly la rge va ria tionin muscle glycogen cont ent ca n be found w hen repeat edbiopsies are taken from the same muscle. Furthermore,during CHO ingestion, glycogen breakdown may con-tin u e at th e sam e h ig h rate in so m e m u scle s, m ay b e

reduced in other muscles, a nd in some muscles glyco-gen synt hesis ma y even occur especia lly a t low exerciseintensities. The third a im of this study therefore wa s touse the indirect sta ble-isotope tr a cer a pproach to get a ne stim ate of m u scle g lycog e n o xid at ion at th e wh o lebody level and to investigate the effect of CHO inges-tion during prolonged exercise on muscle glycogenoxidation.

In summa ry, the a ims of the present study w ere 1) t oe xam in e th e e f fe ct o f sm all an d larg e CHO fe e d in g sdurin g exercise on EG P, 2) to study wheth er entr a nce ofg lu cose in th e syste m ic circulat io n is a ra te -l im itin gst ep for exogenous CH O oxida tion, an d 3) to in ve stigat ewhether high doses of CHO feedings during exercise

can r educe th e ra te of muscle glycogen oxidat ion.To st udy t he aforement ioned quest ions, well-tr a ined

cyclists ingested 13C-labeled CHO during 2 h of exer-cise, and at the same time, a primed continuous infu-sion of [6,6-2H 2]g lucose wa s g ive n . F ro m th e [6,6-2H 2]g lu cos e t r a c er t h e t ot a l R a of glucose could bed e t e r m i n e d , w h e r e a s t h e [13C]g lu cose e n ab led u s toc a l c u l a t e t h e R a g lucose fro m th e g u t (R a g u t ) . B ysu b tractin g R a gut from tota l Ra of glucose, an estimateof EG P wa s ob tain e d .

MATERI ALS AND METHODS

Subjects. Six highly tr ained cyclists aged 21.8 0.2 yr a nd

wit h a w eight of 72.8 2.6 kg volunt eered for th is stu dy. Afterthe na ture a nd the risks of the experimenta l procedures wereexplained t o the subjects, their writ ten informed consent w asobt a ined. The s t udy w a s s ubmit t ed for a pprova l t o t he loca lMedical Ethical Committee.

Pretesting. The VO2 m a x of the subjects was measured on anelectromagnetically braked cycle ergometer (Lode ExcaliburSport , G roningen, The Net herla nds ) during a n increment a lexhaust ive exercise test (31) 1 wk before th e fi rst experimen-t a l t r i a l a n d a v e r a g ed 7 7 2 m l k g1 m i n1. The ma xima lw orkloa d a t t a ined w a s 434 15 W. The results of this testw e r e u s e d t o d e t e r m i n e t h e 5 0 % VO2 m a x w o r kl oa d of t h eexperimental trials.

Exper i ment al t r ia ls . Each subject performed three exerciset r i a l s, e a c h s e pa r a t e d b y a t l ea s t 7 d a y s . Th e o r d er of t h et r ia ls w a s det ermined by count erba la ncing. Ea ch t r ia l con-sisted of 120 min of cycling at 50%VO2 m a x. S ubjects ingesteddrinks conta ining no glucose (FAST), a 4% glucose solution(LO-G lc), or a 22% glucose solution (HI -G lc). S ubjects wereins t ruct ed not t o cons ume a ny product s w it h a high na t ura labundance of 13C d uring t he entire experimenta l period. This

i s t o m i n im i z e a s h if t i n b a c kg r ou n d e n r ic hm e n t d u e t ocha nges in endogenous s ubs t ra t e ut i l iza t ion (54). Furt her-more, subjects were instr ucted to keep their diet a s consta ntas possible the da ys before the tria ls. All subjects performedan ad ditional test for correction for exercise-induced changesin background enrichment w ith sta nda rd procedures (2729,54).

Protocol. Subject s report ed t o t he la bora t ory a t 8: 00 A Maft er an overnight fast . A Teflon catheter (Ba xter Quick Cat hD u P o n t , U d en , Th e N et h er la n d s ) w a s i ns er t ed i nt o a nan tecubital vein, and at 8:30 AM, a resting blood sample of 10ml w a s dra w n. R es t ing brea t h s a mples w ere collect ed (Oxy-con , M ijn h a r d t , M a n n h ei m , G e r m a n y ), a n d v a cu t a i n e rt ubes w ere fi lled direct ly from t he mixing cha mber t o det er-mine t he 13C-to-12C ra tio in expired CO2. At 8:50 AM, su bjects

sta rted a wa rm-up of 5 min at 100 W. At 8:55 AM, a sodiumbicarbonat e prime wa s g iven (5.5 mol/kg NaH 13C O3; C a m -bridge I s ot ope L a bora t ories , Andover, M A), follow ed by a[6,6-2H 2]glucose (Cambridge Isotope Laboratories)prime. Thedoses of the prime were equa l to th e amount of isotope infusedduring 1 h. After the glucose pool was primed, a continuousinfusion of sterile pyrogen-free [6,6-2H 2]glucose w a s s t a r t edvia a calibrated IVAC 560 pump (Ivac, San Diego, CA). Theconcentration of isotopes in the infusate was determined forea ch experiment t o ca lcula t e t he exa ct infusion ra t e. Theinfusion rates were 0.526 0.009, 0.775 0.014, and 1.310 0.041 mol kg1 m i n1 for FAST, LO-G lc, an d HI -G lc, respec-tively.

At 9:00 AM, the w orkload wa s increased t o 50%VO2 m a x for120 min. During t he fi rs t minut es , s ubject s dra nk a n init ia l

bolus (8 ml/kg) of one of the glucose solutions. Thereaft er,every 15 min, a beverage volume of 2 ml/kg w as provided.This feeding schedule has been shown to result in h igh ra tesof ga s t r ic empt ying (42). The a vera ge a mount of glucos eprovided during t he 120 min of exercis e w a s 7 0 g i n t h eLO-G lc trial a nd 350 g in the H I-G lc trial. Blood samples weredrawn at 15-min intervals until the end of exercise. Expira-t ory ga s es w ere collect ed every 15 min. R es ult s of s t a ble-is ot ope a na lys es w ill be pres ent ed for t he 45- t o 120-minperiod beca us e t hos e va lues gua ra nt eed a n is ot opic s t ea dystate (Fig. 1).

Glu cose solu t i ons. The CHO ingest ed w a s corn-derivedglucose (Amylum, B elgium) of high na tura l 13C a bunda nce. As m a l l a m o u n t of [U -13C]glucose (99%, Ca mbridge IsotopeL a bora t ories ) w a s a dded t o t hes e CHO s olut ions . The exa ct

enrichment of the ingested drink wa s measured (after drying)by on-line combust ion-isotope ra tio ma ss spectrometr y (Car lo-Erba -Finniga n MAT 252, B remen, Germ an y) an d wa s 131.69vs. P ee Dee B ellemnite (P DB ) for LO-Glc an d 10.92 vs . P D B for HI -G lc. S ubject s ingest ed 71 3 g /120 m in ofglucose during L O-Glc a nd 354 13 g/120 min of g lucoseduring H I-G lc. The calculated ra tes of CHO ingestion duringt he s econd hour w ere 33 1 g/60 min during LO-G lc a nd164 5 g /6 0 m i n d u r in g H I -G l c . Th e a m o u nt of w a t e ringes t ed w a s s imila r in a l l t r ia ls a nd a vera ged 1, 602 56ml /120 m in .

Analysis . B lood sa mples (10 ml) were collected int o ED TAt u b e s a n d w e r e i m m e d i a t e l y c e n t r i f u g e d f o r 4 m i n a t 4 C

E673CH O I N G ES T I O N CA N CO M P L ET EL Y S U P P R ES S EG P


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(1,000 g). Aliquot s of pla s ma w ere immedia t ely frozen inliquid nit rogen a nd s t ored a t 40C until analysis of glucose(Roche, U ni Kit III , 0710970), free fat ty acids (FFA; WakoNEFA-C test kit, Wako Chemicals, Neuss, Germany), glycerol(Sigma, GPO trinder 337), and triacylglycerols (plus mono-a nd dia cylglycerols ) (Sigma , G P O t r inder 337), w hich w ereperformed w it h t he COB AS B I O s emia ut oma t ic a na lyzer (L aRoche, Basel, Switzerland). Insulin was analyzed by radioim-munoa s s a y (Nuclila b U lt ra s ens it ive Huma n I n s ulin R I A kit ).

B rea t h s a mples w ere a na lyzed for 13C-to-12C r a t i o b y g a schromatogra phy continuous fl ow isotope rat io mass spectrom-etry (Finnigan MAT252, Bremen, Germany). For determina-

t ion of 13C-to-12C r a t i os of p la s m a g l uc os e, g l ucos e w a sderiva t ized t o i t s pent a a cet a t e deriva t ive w it h previous lydes cribed procedures (57). Therea ft er, t he deriva t ive w a smea s ured by ga s chroma t ogra phy-is ot ope ra t io ma s s s pec-trometry (Finnigan MAT 252). By establishing the relation-ship between the enrichment of a series of glucose stan da rdsof va ria ble enrichment a nd t he enrichment of t he glucos epentaa cetate derivat ive of these stand ar ds, the enrichment of

plasma glucose samples wa s determined. This procedure wa sdescribed previously (29).P l a s m a [2H]glucose enrichment w a s det ermined by ga s

chroma t ogra phy-ma s s s pect romet ry a na lys is of t he glucosep e n t a a c e t a t e d e r i v a t i v e s o n a n I N C O S ( F i n n i g a n I N C O S -XL). For [2H]glucose enrichment , ion ma sses of 200 and 202were selectively m onitored.

From indirect calorimetry [respirat ory quotient; O2 upt a keVO2] a nd s t a ble-is ot ope mea s urement s (13C /12C ; 2H enrich-ment ), t ot a l energy expendit ure a nd oxida t ion ra t es of t ot a lfat , total C HO, a nd exogenous glucose were calculated a s wella s R a an d ra te of disappeara nce (R d ) of glucose.

Calculat ions. F r o m C O2 production (VC O2) a n d VO2 t ot a l ,CH O and fat oxidat ion ra tes were calculat ed with the nonpro-tein respiratory quotient (36).

From t he [2H]glucose tracer, the tota l Ra

a n d Rd

of glucosewere calculated with the single-pool non-steady-state equa-tions of Steele (50) as modified for use with stable isotopes(57). Tota l R a glucose represents the splanchnic R a glucosefrom inges t ed CHO a nd l iver a nd pot ent ia lly s ome kidneyglycogenolysis and gluconeogenesis.

The [U-13C]glucose tracer in the drinks was used to calcu-l a t e t h e R a of glucose from the gut and oxidation rates. The13C isotopic enrichment in breath and plasma was expresseda s t he delt a per t hous a nd dif ference bet w een t he 13C-to-12Cra t io of t he s a mple a nd a know n la bora t ory reference s t a n-da rd a ccording t o t he formula of Cra ig (12). The 13C w a srela t ed t o t he int erna t iona l s t a nda rd P DB (P D B -1).

The R a glucose into the plasma of the ingested [13C]glucose(g u t R a ) w a s d et e rm i ne d b y t r a n s pos it i on of t h e S t e el ee qu a t i on a n d t h e k n ow n 13C e n r ic hm e n t o f t h e i n g es t e dglucose (41) and w as ad apted for use with sta ble isotopes

F 2 R a

[(E pl2 E pl 1)/2 (C 2 C 1)/2 (E pl2 E pl 1)/(t2 t1)V ](1)

w h e r e F 2 i s t h e R a of [13C]glucos e in t he blood; R a i s t h e

previously determined t otal R a of glucose (E q. 3); E pl1 a n d E pl 2a r e t h e 13C enrichment s of pla s ma glucose a t t ime point s t1a n d t2, respectively; an d C 1 a n d C 2 ar e glucose concentra tionsa t t1 a nd t2, respectively, and V is volume of distribution.

K n ow i n g t h e R a of [13C]glucose in t he blood, one ca n

det ermine t he a bs orpt ion ra t e of glucos e from t he gut fromthe known enrichment of the ingested glucose

R a gut F 2 /E ing (2)

w here R a gut is t he R a of gut-derived glucose a nd E in g is t he13C enrichment of the ingested glucose.

The ra t e of EG P w a s ca lcula t ed a s t he dif ference bet w eent ot a l R a a nd t he R a from the gut

E G P R a t o t a l R a gut (3)

The 13C O2 production (V13C O2) from t he t ra cer inges t ionw a s ca lcula t ed a s

V13C O2 (molkg1 m i n1) (E CO 2 E bkg ) VC O2 (4)

Fig. 1. Isotopic enrichments in brea th a nd plasma during exercisewit hout ingestion of glucose (FAST; open circles), w ith ingestion ofm od er a t e a m ou n t s of g lu c os e (L O -G lc ; s h a d e d c ir c le s ), or w i t hingestion of large amounts of glucose (HI-Glc; filled circles). Isotopicsteady state was achieved in all conditions during 45-to 120-min timein t e r v a l . P D B , P e e D e e B e l le m n it e ; b k g , b a c k g r ou n d ; A P E, a t ompercent excess; pm , .

E674 CH O I N G ES T I O N CA N CO M P L ET EL Y S U P P R ES S EG P


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w here E CO 2 is t he brea t h13C-to-12C ra t io a t a given t ime a nd

E bk g is t he ba ckground brea t h 13C-to-12C ra t io a t res t beforeglucose tr acer ing estion. The conversion factor is 1 mol C O2equa ls 22.4 liters.

Plasma glucose oxidation was calculated as

plasma glucose oxidat ion

5V13C O2 /[(E pl2

E pl1

)/2 E bkg ]6 (1/k)(5)

w h e r e k 0.7467 liters C O2/g glucose, wh ich is th e am ount ofC O2 (in lit ers) produced by t he oxida tion of 1 g of glucose.

Muscle glycogen oxidation w as ca lculated a s the differencebetw een tota l CHO oxidation and pla sma glucose oxidat ion.

Exogenous CHO oxida t ion w a s ca lcula t ed w it h t he know nenrichment of t he inges t ed glucos e a nd t he 13C O2-to-

12C O2ra t io in brea t h

exogenous glucose oxidation

VC O2 (E CO 2 E bkg )/(E ing E bkg )(1/k)(6)

w here E bkg is t he13C enrichment of expired air a t rest , before

glucose ingestion, E CO2

is the 13C enrichment of breat h during

exercis e a t different t ime point s , a nd E in g i s t h e 13C enrich-ment of the ingested glucose.

From t ot a l CHO oxida t ion a nd exogenous glucos e oxida -tion, endogenous CHO oxidat ion can be calculat ed.

B ecause the endogenous glucose oxidat ion is derived fromeither muscle glycogen or liver (and kidney) glucose duringexercise, endogenous glucose oxidat ion w as calculated a s th edifference bet w een endogenous CHO oxida t ion a nd mus cleglycogen oxidation.

The metabolic clearance rate (MCR) was calculated as theR d of glucose divided by the average glucose concentrationover th at t ime period

M CR (mlkg1 m i n1) R d/[(C 1 C 2)/2] (7)

The percentage of glucose disappearing from the plasmathat is oxidized was calculated as

%R d oxidized (pla sma glucose oxida tion/R d) 1 00% (8)

Statist ics. Throughout t his s t udy glucose kinet ics w ereca lcula t ed bet w een t w o dif ferent t ime point s (t1 a nd t2); inFigs . 18 a nd Ta bles 1 a nd 2, how ever, t hes e va lues w erepres ent ed a s t2. For ins t a nce, R a a t t 60 in rea li t y is R abetw een 45 and 60 min.

A t w o-w a y (t rea t ment t i m e) a n a l y s is of v a r i a n ce f orrepeated mea sures wa s performed to study differences amongt he t hree condit ions. A B onferroni-Dunn pos t hoc t es t w a sapplied in case of a signifi cant (P 0.05) F ra t io t o loca t e t hedifferences.

RESULTS

Plasma glucose, in suli n, fr ee fatt y acids, glycer ol, andtriacylglycerol. In the FAST tria l, plasma glucose con-centra tions w ere in the ra nge of 4.24.6 mmol/l a t r esta nd t hroughout th e exercise bout (Fig. 2). With glucoseingestion in the HI-Glc trial, plasma glucose concentra-tions peaked within the first 15 min of exercise at 6.0 0.2 mmol/l. P la sma glucose concentr a tions w ere higherthr oughout exercise with HI -G lc compa red w ith FAST(and LO-Glc), but this only reached statistical signifi-can ce a t 15, 105, and 120 min (P 0.05).

Plasm a in su lin was lo w at re st an d d u rin g e xe rcisew hen s ubjects w ere fa st ed (i.e., 5 7 U /ml) (Fig . 2) butwas significantly elevated by glucose ingestion duringe xe rcise (F ig . 2). Th e h ig h est in su lin valu e s we reobserved a fter 15 min (8 2 U /ml w ith LO-G lc a nd11 4 U /ml w ith H I-G lc). P la sma insulin decrea sed inal l tr ials b u t r e m ain ed e levat e d in th e HI -G lc tr ia ls incom p arison with F AS T. A t 60 m in , in su lin wa s alsosignificantly higher during HI-Glc compared with LO-Glc. In all conditions, plasma insulin decreased to orbelow the resting fasting level at the end of the trials.During FAST and LO-Glc, insulin levels were very low(i.e., 2 3 U /ml) tow a rd t he end of exercise.

Re stin g p lasm a F F A con ce n trat ion s we re b etw e en337 an d 420 mol/l. Dur ing t he FAST tr ia l, plasm a FFAcon cen tra t ion in i t ial ly d e cre ase d d u rin g th e fi rst 10min an d thereaft er gradua lly increased during exerciseto about three times basal level (854 104 mol/l a t120 min; Fig. 3). P la sma FFA in both glucose condit ionsfol lowe d a s im ilar p att e rn a n d w as su pp ressed d u rin gLO-Glc (to 623 70 mol/l a t 120 min) compa red w it hFAST a nd even more durin g HI -G lc (to 382 70 mol/la t 120 min; P 0.05). Fr om 30 to 120 min, pla sma FFAwas sig n ifi can tly lo we r d u rin g HI - G lc co m p are d withFAS T.

Fig. 2. Plasma glucose and insulin concentrat ions during exercisewit hout ingestion of glucose (FAST; open circles), w ith ingestion ofm ode r a t e a m ou n t s of g lu cose (L O -G lc ; s h a d e d c ir c le s), or w i t hingestion of lar ge am ounts of glucose (HI -G lc; filled circles). a S ig n ifi -c a n t (P 0.001) difference betw een H I-Glc a nd FAST; c significant(P 0.001) difference between HI -G lc an d L O-G lc.



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Plasma glycerol concentrations were increased dur-ing exercise from resting va lues in the r a nge of 5872

to 474 48 mol/l a t 120 min dur ing FAST, 310 39mol/l durin g LO-G lc, a nd 203 42 mol/l dur ingH I-G lc (Fig. 3; P 0.05).

The pla sma tria cylglycerol concentr a tion at rest w a s0.5 0.1, 0.4 0.1, and 0.4 0.1 mm ol/l for FAST,LO-Glc, and HI-Glc, respectively, and did not changedurin g exercise (Fig. 3). After 120 min of exercise, t heva lues were 0.3 0.1, 0.3 0.1, and 0.4 0.1 mm ol/l,respectively. No differences were observed in tr ia cylglyc-erol concentr a tion between t ria ls.

Whole body CH O and fat oxidati on. VO2 w a s s i m il a rduring each exercise session (3738 mlkg1 m i n1)

and elicited 49 2%VO2 m a x (Ta ble 1). The r espira t oryexcha nge ra tio decreased in the FAST trial (P 0.05)an d re m ain e d sta b le with G lc in g e stion . Th e re sp ira-tory exchange rat io wa s slightly higher with t he HI-G lcfee d in g (Tab le 1). CH O oxid at ion d e cre ase d d u rin gFAST, decrea sed less with L O-G lc, a nd rema ined sta blewith HI-Glc (Fig. 4). After 120 min of exercise, totalCH O oxidat ion ra tes w ere 100 5 (1.31 0.07 g/m in ),118 5 (1.55 0.07 g/min ), a nd 153 9 mol kg1 m in1 (2.00 0.12 g/min) for FAST, LO-G lc, a ndH I-Glc, respectiv ely (Fig. 4; Ta ble 1). Tota l fa t oxida tionwas markedly suppressed by the Glc feedings (Fig. 4;P 0.05). After 120 min of exercise, tota l fa t oxida tionrat e s we re 48 2 (0.63 0.01 g /m in ), 41 1 (0.54 0.01 g/mi n), a nd 33 2 mol kg1 m i n1 (0.43 0.01g/min ) for FAST, LO -G lc, a nd H I-Glc, r espectively (P0.05).

Stabl e-isotope m easur em ent s. G l u cos e i n g es t i o nraised 13C O2-to-

12C O2 breat h ra tios from va lues a round26.6 vs. P DB to va lues betw een 8 a n d 21 vs. PDB during LO-Glc and HI-Glc, respectively. The

b r ea t h r a t i os d u ri ng t h e ex pe ri m en t a l t r i a ls w i t h[U -13C] g lu co se trace r in g e stio n are sh o wn in F ig . 1 .Glucose 13C enrichment w a s elevat ed by the [U -13C]glu-co se trace r in g e stio n an d was stab le b e twe e n 45 an d120 min. Plasma glucose 2H e n rich m e n t was b e twe e n1.7 an d 2.0%, a n d th e re w as also a n isoto pic ste ad ysta te betw een 45 and 120 min.

Ra a n d R d of plasma glucose and MCR. B o th R a a n dR d glucose w ere ma rkedly elevat ed w ith glucose inges-tion (45% wit h LO-G lc a nd 143% wit h HI -G lc; P 0.001; Tab le 2; F ig . 5). D u rin g th e se con d h ou r ofexercise, no changes in R a or R d glucose w ere observedover time, although during HI-Glc, R a a n d R d glucoseha d a tendency to increase t owa rd t he end of exercise.

This however did not reach st a tist ica l significa nce.M C R w a s 7 1 m l k g1 m i n1 d u rin g FAS T a n d wa ssignificantly higher during LO-Glc (10 1 m l k g1 m in1; P 0.001) and even higher during HI -G lc (151 ml k g1 m i n1; Ta ble 2; P 0.001).

Glucose Ra f r om t h e gu t a n d E G P . The R a g u t w a s3132 molkg1 m i n1 (0.410.42 g/min ) dur ing th esecond hour of the LO-G lc tria ls a nd 7379 mol kg1 m in1 (0.961.04 g/min ) dur ing t he H I-Glc t ria l (Fig. 5;Ta ble 2). This d ifference wa s highly signifi cant (P 0.0001). E G P wa s 3032 mol kg1 m i n1 (0.400.42g/min) during FAST a nd w a s suppressed by th e LO-G lcfeedings to 1213 mol kg1 m i n1 (0.16 0.17 g/mi n).Ingestion of large amounts of glucose during exercise

(HI-Glc) resulted in increased R a gut and completelysuppressed E G P (Fig. 5; Ta ble 2). The effects of CH Ofeedings on the R a of glucose are summarized in Fig. 6.With FAST, a ll glucose a ppearing in t he circulat ion isfrom the liver; during LO-Glc, EGP is suppressed andg lu co se is d e rive d b o th fro m l ive r an d g u t . With th eingestion of lar ge a mounts of glucose (HI -G lc), t he R aglucose is increa sed even th ough EG P is completelyblocked.

Oxidation of plasma glucose. Plasma glucose oxida-tio n was b e twe e n 22 an d 26 m o l k g1 m i n1 (0.310.34 g /m in ) d u rin g L O-G lc an d b etw e en 58 a n d 72

Fig. 3. Plasma free fa t ty acids (FFA), glycerol, and triacylglycerolconcentra tions du ring exercise without ingestion of glucose (FAST;open circles), wit h ingest ion of moderat e am ounts of glucose (LO-Glc;sha ded circles), or with ingestion of large a mounts of glucose (HI -G lc;fi lled circles). a S ig n ifi c a n t (P 0.001) difference between HI -G lc an dFAS T; b s ig n ifi c a n t (P 0.001) differen ce betw een LO-Gl c an d FAST.



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molkg1 m i n1 (0.760.94 g/min ) dur ing H I-Glc (Fig.6; Ta ble 1). At a ll times, pla sma glucose oxida tion w a ssignificant ly higher during HI-G lc (P 0.0001). Plasmaglucose oxida tion w a s not mea sured dur ing FAST, butw e a s s um ed t h a t i t w a s 96 99% of R d g lu cose asobserved in a previous study (29). P lasma oxidat ionwas not significantly different from R d glucose, and thep e rce n tag e o f R d o xid iz e d was b e twe e n 92 an d 95%during t he las t 30 min of exercise.

M uscle glycogen oxid ati on. Muscle glycogen oxida -tion (tota l CH O oxidat ion plasma glucose oxidation)did not change as a function of CHO ingestion duringL O- G lc an d HI - G lc an d re m ain e d b e twe e n 77 an d 89molkg1 m i n1 (1.011.17 g/min) during the lasthour of exercise (Fig. 7; Table 1). This represented69%of tota l CH O oxida tion dur ing LO-G lc and 56%oftota l CHO oxidation during HI-G lc.

Exogenous CH O oxidati on. O x i d a t i o n r a t e s o f t h ein g e ste d CHO we re also re lat ive ly stab le d u rin g th esecond hour of exercise (Fig . 7, Ta ble 1). D ur ing L O-G lc,exogenous glucose oxidat ion ra tes w ere betw een 22 and26 mol kg1 m i n1 (0.310.34 g/min), a nd th is w a sincreas ed to 5872 mol kg1 m i n1 (0.76 0.94 g/m in )during HI-Glc. An overview of substrate oxidation is

given in Fig. 8.

DISCUSSION

Effect of CHO ingestion on EGP. Ingestion of moder-a te a mounts of glucose (35 g/60 min) ma rkedly sup-p re sse d EG P. With th e in g e stio n o f larg e am o u n ts o fglucose (175 g/60 min), E G P w a s completely blockeda n d a l l g lu cos e a p pe a r i ng i n t h e p la s m a or i gi n a t e dfrom th e ingested C HO . With th e use of a [6-3H]glucoseand a [6,6-2H ]glucose t ra cer, McConell et a l. (34) founda 51% r e du ct i on i n E G P w h e n 200 g of C H O w e r e

F i g. 4 . Wh ol e b od y ca r b oh y d r a t e (C H O ) a n d f a t o xi da t i onr a t e s d u r in g e xe r ci se w i t h ou t i n ge st i on of g lu cos e (F AS T;o pe n ci r cl es ), w i t h i n g es t i on o f m o de r a t e a m o u n t s o f g l uc os e(LO-Glc; sha ded circles), or w ith in gestion of larg e amoun ts of glucose(HI-Glc; filled circles). a S ig n ifi c a n t (P 0.001) difference betw eenHI-Glc and FAST; b significant (P 0.001) difference between LO-Glcand FAST; c s ig n i fi c a n t (P 0.001) difference between HI-Glc andLO-Glc.

Ta ble 1. Oxygen u ptak e, respir atory exchange r ati o, CH O oxidat ion, pl asma glu cose oxid ati on, exogenous CH Ooxidation, and glycogen oxidation during exercisewithout CHO ingestion, with LO-Glc,or w it h in gesti on of HI -Glc

TimeInt e r v a l ,

mi nVO2 ,

m l k g1 m i n1

RespiratoryEx c ha ng e

R a t i o

Tota l CH OOxidation,

molkg1 m i n1

P l a s m aGlucose

Oxidation,molkg1 m i n1

ExogenousGlucose

Oxidation,molkg1 m i n1

GlycogenOxidation,

molkg1 m i n1

FAST75 90 371 0.8190.004 1104 303 00 81490 105 381 0.8180.007 1138 303 00 839

105 120 381 0.8070.005 1005 313 00 694

L O - G l c

75 90 371 0.8320.004 1194 362 242 83590 105 371 0.8370.003 1205 411 262 786

105 120 371 0.8310.004 1185 403 253 774

H I - G l c

75 90 371 0.8630.005* 1466* 684* 653* 80890 105 381 0.8650.005* 1527* 725* 703* 813

105 120 381 0.8640.007* 1539* 726* 723* 823

Values ar e means S E . VO2 , oxygen uptake; CHO, carbohydrates; LO-Glc, ingestion of moderate amounts of glucose; HI-Glc, ingestion oflar ge am ounts of glucose; FAST, ingestion of wa ter only. *Sign ifi cant difference betw een HI-Glc an d FAST; signifi cant difference betw een

LO-Glc and FAST; signifi cant difference betw een HI-Glc and LO-G lc; P 0.001.



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ingested during 2 h of exercise at 69% VO2 m a x (100 g

CH O/h ). S im ilar ly, B o sch e t a l . (3) re porte d a 70%re d u ctio n in EG P wh e n 150 g o f CHO we re in g e ste d

durin g 3 h of exercise a t 70%VO2 m a x (50 g C H O/h).Th e se resu lts a re com p ara b le with th e L O-G lc t r ial

in th e p re se n t s tu d y. I n th e ir s tu d y (3) , th e e xe rcisei n t e n s i t y , a n d t h u s t h e a b s o l u t e r a t e s o f E G P , w e r ehigher t ha n in th e present stu dy. To our know ledge, nos t u d y h a s s h ow n p r ev iou s ly t h a t i n ge st i on of l a r g ea mounts of glucose ca n completely suppress E G P. Therema y be severa l rea sons for this suppression. Althoughthe present tracer method cannot distinguish betweenliver glycogenolysis a nd gluconeogenesis, i t is likelyth a t d u rin g L O-G lc b oth p rocesses we re in h ib i ted .During HI-Glc, both gluconeogenesis and glycogenoly-

sis were blocked. We suspect that the effect of glucoseingestion is m a inly on glycogenolysis becau se gluconeo-g e n esis m ay b e n e g lig ible in th e p rese n t con d it ion s.P re viou sly, we u sed tw o d i f fe ren t isoto pic tra cers toestima te gluconeogenesis (glucose ca rbon r ecycling) inan id en tical e xp erim en ta l se tu p a s t h e p rese n t s tu d y(29), and it was concluded that gluconeogenesis wasnegligible in these conditions. I t has been suggestedth a t in cre ase s in p lasm a g lucose con ce n trat ion an dplasma insulin levels are major factors reducing EGPd u rin g e xercise . H owe ver, in th e p rese n t s tu d y, th eplasma glucose concentr a tion wa s only slightly higherduring HI -G lc compar ed w ith LO-G lc a nd FAST. Al-t h o u g h i t h a s b e e n s h o w n t h a t p l a s m a g l u c o s e m a y

inhibit E G P d irectly (26, 46), plasm a glucose concent ra -tions were much higher in t hose studies compar ed wit hth e p re sen t s tu d y in w h ich con cen tra t ion s d u rin g th esecond hour of exercise were always between 4.5 and5.5 mmol/l. In crea sed insulin levels ma y be a morereasona ble explana tion for the reduced EGP a fter CHOi n ge st i on . I t h a s b ee n r e por t e d t h a t i n su li n or a nin cre ase d in su lin -to -g lucag on ra t io can in h ib i t EG P(55). Insulin levels were significantly elevated duringexercise wit h H I-G lc, an d it is possible tha t even sma llchanges in insulin have a potent effect on E G P. In thisstudy, we did not m easure glucagon or epinephrine or

cortisol. McConell et a l . (34), however, showed tha t

during the second hour of exercise, gluca gon an d epi-n e ph rin e levels w e re lowe r af te r CHO in g estion , a n dth e y su g g est th a t th e se factors m a y a lso h ave con trib -uted to the reduction in EGP. Recently, Hevener et al .(24) demonstra ted t ha t glucosensors in the porta l veinare largely responsible for the detection of the portalglucose concentration, which then results in a portal-sym p ath e tic g lu core g ulato ry re fle x (i .e ., re d u ce d orincreased hepatic glucose production). Whatever them e ch an ism , th e p re se n t s tu d y su g g e sts s tro n g fe e d -b a c k r e g u l a t i o n o f E G P t h a t h e l p s m a i n t a i n p l a s m aglucose concentr a tion in a na rrow r a nge.

Glucose uptake and MCR are markedly increased byglu cose i ngestion. A second importa nt factor t ha t helps

m a i n t a i n p la s m a g lu cos e con cen t r a t i on w h e n l a r g eamounts of glucose are ingested is the increased glu-cose uptake. I t has been reported that at low exerciseintensities, glucose ingestion increases leg glucose up-take (1). Here, the R d glucose increa sed along w ith thet ot a l R a g lu co se (EG P an d R a gut). The mechanismsb e h in d th is in cre ase d g lu co se u p tak e are larg e ly u n -k n o wn b u t m ay, in p art , b e d u e to in cre ase d g lu co secon cen t r a t i on t h a t t h r ou g h m a s s a c t i on m a y d r iv eglucose int o th e cells (21).

However, our observat ion t ha t MC R (Rd/pla sma glu-co se co n ce n trat io n ) was sig n ifi can tly in cre ase d withCHO fee din g s d o es n ot su p port th is n otion . Th e in -cr e a s ed M C R w i t h i n cr ea s i n g a m o un t s of i n ge st e d

CHO su g g ests th a t p lasm a g lu cose a vai lab i li ty (i .e. ,con cen tra t ion ) is n ot th e sole d rivin g force for th eincrease in plasma glucose uptake and oxidation dur-in g e xe rcise with CHO in g e stio n . Plasm a in su lin washigher during exercise during H I-G lc, a nd contr a ctionsan d insulin have been shown t o have strong synergisticeffects on muscle glucose upt a ke during exercise inhumans (13, 56). Higher insulin levels and contractionboth stimula te G LU T-4 tra nslocat ion, but t hey a ppea rto activate different pools of transporters or differen-tially activate the same pool (39, 40). I t has also beensh own th a t h ig h er in su lin le vels d u rin g e xe rcise in

Ta ble 2. Ra a n d R d of glucose, th e Ra gut, H GP, M CR, and per cent age of Rd glucoset hat was oxid ized

TimeInt e r v a l , m i n

R a Glucose,molkg1 m i n1

R d Glucose,molkg1 m i n1

R a G u t ,molkg1 m i n1

H G P ,molkg1 m i n1

M C R,m l k g1 m i n1

%RdOxidized

FAST

75 90 313 313 00 313 7190 105 313 313 00 313 71

105 120 323 323 00 323 81

L O - G l c

75 90 452 452 322 131 101 82690 105 442 442 312 121 101 946

105 120 453 443 322 132 101 9210

H I - G l c

75 90 743* 743* 743* 00* 151* 93990 105 774* 774* 774* 00* 151* 9510

105 120 794* 794* 794* 00* 161* 9211

Values ar e means S E. R a a n d R d , ra tes of appearance a nd disappeara nce, respectively; Ra gut , ra te of appearance of glucose in gut ; H GP,hepat ic glucose production; MCR, meta bolic cleara nce rate. * Signifi cant d ifference between HI-Glc and FAST; signifi cant d ifference betweenLO-G lc and FAST; signifi cant difference betw een HI-Glc and LO-Glc; P 0.001.



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com b in ation w ith lo we r fat t y a cid le vels m a y a ctivat ephosphofructokinase a nd pyruva te dehydrogenase; th isma y lead to lower glucose 6-phosphat e concentr a tion,which, in turn, will increase glucose uptake (17). An-other factor tha t ma y ha ve contributed to the increa sedg lu co se u p tak e an d M CR m ay b e th e lo we r fat ty acidlevels. CHO ingestion during low- to moderate-inten-si ty e xe rcise in h ib i ts l ip olysis (11, 25) an d th e re bya t t e n u a t e s t h e i n c r e a s e i n f a t t y a c i d c o n c e n t r a t i o n .Increases in plasma fat ty a cid levels ma y inhibit muscle

glucose uptake directly by yet unknown mechanisms(20), although others did not find an effect of plasmafatty acid concentration on glucose uptake during exer-cise at 60%VO2 m a x (35).

I t is u n lik ely, h o we ver, th at th e lo we r p lasm a fat t ya cid levels during H I-G lc w ere responsible for t he lar geincreases in MCR. On t he other ha nd, it is possible tha tthe lower fa tt y acid concentra tions may ha ve fa cilita ted

t h e i n su li n a n d t h a t con t r a c t i on i n du ce d i n cr e a s edmuscle glucose upta ke.

An a d d it ion al re m ark t h at can b e m ad e with r e gar dto the MCR in the present study is that the calculationof MCR overcorrects for the mass action effect glucosehas on stimulating its own disappearance. The reasoni s t h a t t h e cl ea r a n ce c a l cu la t i on a s s u m es a l in ea rr e la t i on s h ip b et w e en c on ce n t r a t i on a n d u p t a k e,wh e re as th e re lat ion sh ip is in fact curvi lin ear. Th u s,even if a t reat ment ha s no effect on the intrinsic abilityof t issues to ta ke up glucose, ca lculat ed glucose clea r-ance will tend to be lower when concentration is highera n d v ice v e r s a . Th er ef or e , t h e f a ct t h a t w e f ou n d ah i gh er M C R ev en t h ou g h t h e con ce nt r a t i on i s 1mmol/l higher d uring HI -G lc is all t he more impressive.

Limitations of exogenous CHO oxidation. M a x i m a le xog en ou s CH O oxidat ion wa s 72 m ol k g1 m i n1

(0.94 g/min) in th e present stu dy. This is in a greementwith several other studies that employed either radioac-tiv e (3, 23) or s t a ble isotopes (27, 28, 37, 54) to q ua nt ifyexogenous CHO oxidation during exercise. From thosestudies, it appeared that exogenous CHO oxidation islimited to 1 g/min a s review ed by H a w ley et a l. (22).E v en w h en l a r ge a m ou n t s of C H O w e r e i n ges t ed ,oxida t ion ra t es did n ot exceed 1 g/min (43, 54). H ere w ecalcula ted CH O ingestion t o be 2.15 g/min during thesecon d h ou r, b u t e xog e n ou s CH O oxidat ion d id n otexceed 0.94 g/mi n.

D u rin g L O-G lc, R a g u t e q u a l e d t h e r a t e o f C H Oin g estion d u rin g th e se con d h ou r (32 1 v s. 33molkg1 m i n1). R a g u t a n d t h e r a t e o f i n g es t i onwe re 0.43 g/min during LO-G lc. This implies tha t

Fig. 5. Total rat e of a ppeara nce of glucose (R a glucose), the R a ofg lu cose f r om t h e g u t (R a gut), and endogenous hepatic glucoseproduction (HGP ) during exercise wit hout in gestion of glucose (FAST;open circles), wit h ingest ion of moderat e am ounts of glucose (LO-Glc;sha ded circles) or w ith in gestion of large a mounts of glucose (HI -G lc;fi lled circles). a S ig n ifi c a n t (P 0.001) difference between HI -G lc an dFAS T; b significant (P 0.001) difference between LO-Glc and FAST;c significant (P 0.001) difference between H I-Glc an d L O-G lc.

Fig. 6. R a of glucose from the gut (R a gut) or from endogenous sources(HGP) without ingestion of glucose (FAST), with ingestion of moder-at e amount s of glucose (LO-Glc), or with in gestion of large am ounts ofglucose (HI-Gl c).



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absorption was not limiting and the liver did not storeingested glucose, but instead all ingested glucose ap-pea red in the bloodstr eam a nd most of this glucose wa soxidized. When a lar ger dose of CHO w a s ingested, Ragut w as less tha n one-ha lf of the ra te of CHO ingestion(7379 vs. 164 molkg1 m i n1). R a g u t w a s 0 . 9 6 1.04 g /m in , wh e re as CH O w e re in ge ste d a t a ra te o f2.15 g/min durin g t he second hour of exercise dur ingHI -G lc. Th e se n u m be rs in d icat e th a t on ly p ar t of t h ein g este d CH O w il l en te r th e syst e m ic circu lat ion an d

th a t a larg e par t o f th e Ra gut is oxidized. The fa ctor(s)limiting exogenous C HO oxidat ion m ust thus be proxi-mal from the liver. Most likely, R a g u t d u rin g HI - G lcw a s limited by t he ra te of digest ion and/or absorpt ion ofglucose, and a fair a mount remained in the gast rointes-t i n a l t r a c t . P r e vi ou s s t u d i es h a v e s u g g es t e d t h a t t h eabsorptive capacity of the intestine possesses a modestex ces s of n u t r i en t ca p a c it y ov er n u t r i en t i n t a k e i n

resting conditions (47). During exercise, however, ar ed u ce d m e s en t e r ic b lood fl o w m a y r e su lt i n a d e-crea sed a bsorption of glucose a nd wa ter (4). Althoughthis will occur predomina ntly a t higher exercise inten-si t ies (4), d e cre ase d b lood flo w in th e in te st in e m ayhave contributed to a reduced absorption of water andglucose and thus to a low R a g u t re lat ive to th e ra te o fingestion. However, it cannot be excluded that the liverplays a n a ctive role a nd tha t glucose is ta ken up by theliver in the first pass.

M uscle glycogen oxidati on is not reduced by CH Ofeedings. T h e th ird p u rp o se o f th is s tu d y was to se ew heth er ingest ion of 360 g of CH O durin g 2 h of cyclingexercise reduces muscle glycogen oxidat ion at th e wh olebody level. Muscle glycogen oxidation was similar withingestion of either 70 or 350 g of CHO during 2 h ofexercise. These findings corroborate findings from sev-eral st udies with direct measur ements of muscle glyco-gen in muscle biopsies (3, 10, 14, 15, 18) but are inco n trast with o th e r stu d ie s in wh ich CHO in g e stio nhad a glycogen-sparing effect (2, 19, 52, 53). In runners,it wa s sh own tha t CH O ingestion (4550 g/h) reducedt h e n et g ly cog en b r ea k d ow n i n t y p e I fi b e r s d u r i n gru n n in g at 72 76% VO2 m a x, an d th is m ig h t h ave b e e nresponsible for the observed improvements in endur-an ce cap acity (52, 53). Tsin tz as an d Will iam s (51)r ecen t l y a r g u ed t h a t t h e ob s er v ed eff ect s cou ld b esp e cifi c to ru n n in g . Co n tin u o u s cycl in g wo u ld cau se

Fig. 7. P lasma glucose oxidat ion, muscle glycogen oxidat ion, a ndexogenous C HO oxidat ion during exercise w ithout ingest ion of glu-cose (FAST; open circles), with ingest ion of moderate amounts ofglucose (LO-Glc; shaded circles), or wit h ingest ion of large a mounts ofglucose (HI-G lc; fi lled circles). a S ig n ifi c a n t (P 0.001) differencebetween H I-Glc and FAST; b s ig n ifi c a n t (P 0.001) difference be-tw een LO-Glc an d FAST; c s ig n ifi c a n t (P 0.001) difference between

HI-Glc and LO-Glc.

F ig . 8 . S u b s t r a t e oxid a t ion d u r in g e x e r cis e w i t h ou t in g es t ion ofglucose (FAST), with ingest ion of moderate amounts of glucose(LO-Glc), or w ith ingestion of la rge a mount s of glucose (HI -G lc).



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less marked changes in plasma glucose concentrationan d in su lin con cen tra t ion s com p are d with ru n n in g ,and these differences might play an important role inthe effect on glycogen utilization to be observed. How-ever, we observed a relat ively la rge insulin response tothe C HO feedings w hile pla sma glucose concentra tionwas also sl ig h tly in cre ase d . Ye t th is d id n o t re su lt inglycogen spa ring a s proposed by Tsint za s a nd William s.Th er e for e, t h e p r es en t s t u d y s u gg es t s t h a t f a ct or soth e r th a n in su lin ar e re sp on sible for th e d iscre pan tfi ndings in run ning ca pacity (52, 53) a nd cycling (3, 10,14, 15, 18).

In t he present study, CHO feedings w ere provided asa la rge bolus at th e onset of exercise follow ed by sma llerfee d in g s e ve ry 15 m in . I t is p ossible, h owe ver, t h atdifferent feeding schedules would hav e produced slight lydifferent results. Glucose feedings in the hour beforeexercise may lead t o increased insulin concentr a tions,wh e re as fee d in g s late r in e xe rcise m a y com p le telyabolish an insulin response to the CHO feedings. Thepresent feeding schedule, however, will lead to high

rates of gastric emptying (42) and will result in maxi-ma l exogenous CH O oxidat ion ra tes (22, 54).Percenta ge of Rd oxidized. Th e p ercen ta g es of R d

glucose oxidized were high at the end of 2 h of exercise(92 95%), indica tin g th a t lit tle or no glucose is used fornonoxidat ive disposal under these conditions. Theseh ig h rat e s of oxidat ion a re in ag re e m en t w ith a s tu d yby C oggan et a l . (8), w ho found t ha t 93%of R d glucosewas oxidized during exercise at 70%VO2 m a x w h e n C H Ow ere ingested, a nd confirm our previous fi ndings (96100% R d oxidized) (29). Others have found lower per-ce nt a g e s of g lu cos e t a k e n u p a n d ox id iz ed d u r in gexercise at intensities compar able wit h th e intensity inthe present study (50%VO2 m a x) (9, 16, 44). The lower

percent a ges of R d oxidized can most likely be explainedby th e fa ct the bica rbona te pool w a s not primed in thosestudies, which may ha ve led to the entra pment of a fa ira mount of 13C O2 in the bicarbona te pool. This ma y ha vecau se d a m ark e d u n d e re stim atio n o f th e tru e p lasm aglucose oxidation. Other studies in which a bicarbonatep rim e w as g ive n re p ort valu e s m o re com p ara b le witht hose in t he pres ent st udy (8894%) (7).

I t h a s b een r epor t ed t h a t w i t h a 13C t r a c er f orstu d yin g fat t y a cid m e tab o lism , par t o f th e tra ce r m ayb e ( te m p o rari ly) trap p e d in e xch an g e re actio n s witht he tr icar boxylic acid (TCA) cycle (48, 49). For exa mple,some 13C m a y b e i n cor p or a t e d i n t o t h e g l u t a m a t e-gluta mine pool via -ketogluta ra te or into phosphoenol-

pyruva te via oxaloaceta te. This label fixa tion results ina decreased r ecovery of la bel in the expired ga ses, andto correct for th is loss, t he a ceta te correction fa ctor h a sbeen proposed (49). The la bel loss is dependent on t hem e t a b ol ic r a t e , a n d a t h i gh ox y gen u pt a k es (37 38ml/kg in the present study ), less la bel is tr apped a ndrecovery of the [1-14C]a ceta te label wa s 8590% (49).B e sid es th a t , [U-13C]glucose has six labeled carbons ofwh ich tw o wil l ap p ear d irectly in 13C O2 and thereforedo not ent er t he TCA cycle. Only tw o-th irds (66%) of theglucose carbons a re subject t o label fi xa tion. Therefore,th e re covery of carb on s from [U-13C]glucose w ill be

h ig h e r th an th e re co ve ry o f [ 1-13C]palmitate (49) or[U -13C]p alm itat e (48), e xp lain in g wh y we fi n d su chhigh percentages of R d oxidized. The small differencefrom 100%ma y be explained by the a ceta te correctionfactor, implying that all glucose molecules disappear-ing from the plasma might ha ve been oxidized in bothth e presence a nd a bsence of glucose ingestion.

General overview of substrate uti l ization with CHOingestion. The results of the present study indica te th a tglucose ingestion during exercise lea ds t o decreased fa toxidation, partly because of an inhibition of lipolysis(25) a n d an in cre ase d CH O oxidat ion (F ig . 8). Th ei n cr e a s ed C H O ox id a t i on w a s e xp la i n ed b y a n i n -crea sed plasma glucose turnover. The a ppeara nce ofingested glucose in the bloodstream (R a gut) increasedwith the CHO feedings in a dose-dependent way. At thes a m e t i m e, E G P w a s s u pp r es s ed a n d w i t h l a r g e C H Ofeedings w as even completely blocked. This effect ispossibly insulin mediated. The oxidation of ingestedCH O increased t o 0.94 g/min w hen CH O were ingest edat a ra te of 2.15 g/min. Fa ctors t ha t limit exogenous

CH O oxidat ion must be situat ed in the spla nchnic a rea,potentia lly a ga str ointestina l limita tion or retention oflabeled glucose in the splanchnic bed (34). The in-creased CHO oxidation with CHO ingestion was due toincreased glucose uptake and clearance. The increasedclearance may also be insulin mediated. The glucosetha t disa ppeared from the pla sma (and most likely wa stak e n u p b y act ive sk e le tal m u scle ) was larg e ly o xi-dized, a nd very litt le or no glucose wa s directed t owa rdg lycog en syn th e sis . P lasm a g lucose oxid at ion re pre -s en t e d 21% d u r in g L O -G l c a n d 47% of t o t a l C H Ooxidat ion d u rin g HI -G lc, con fi r m in g th a t p lasm a g lu-cos e c a n i n de ed b e a n i m por t a n t s u bs t r a t e d u r in gexercise, as shown by others (3, 10, 45). Muscle glyco-

gen oxidation was not reduced by the glucose feedings.I n su m m ary, we co n clu d e th at sm all CHO fe e d in g s

suppress EG P a nd tha t la rge CHO feedings completelyblock EG P, most likely beca use of increases in plasmain su lin an d p lasm a g lucose con cen tra t ion . Th e e n -trance of glucose into the systemic circulation seems tob e th e l im itin g facto r fo r e xo g e n o u s CHO o xid atio nb eca u s e a l a r g e p e rce nt a g e of R a g u t wa s oxidiz ed ,w herea s only a sm a ll percent a ge of th e ingested glucoseappeared in the bloodstream. Muscle glycogen oxida-tion at the whole body level was not reduced by glucoseingestion dur ing cycling exercise at 50%VO2 m a x.

Address for reprint r equests a nd other correspondence: A. E .

J eukendrup, S chool of S port and Exercise Sciences, U niv. of B ir-m in g h a m , Ed g b a s t on , B ir m in g h a m B 1 5 2 TT, U K (E-m a il : A .E.J eukendru p@bha m.a c.uk).

Received 14 J uly 1998; accepted in fi na l form 1 December 1998.

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carbohydrate ingestion can completely suppress endogenous glucose production during exercise

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