Lipid Faal Am J Clin Nutr-1995-Frayn-250S-61S

7/27/2019 Lipid Faal Am J Clin Nutr-1995-Frayn-250S-61S

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2505 Am J C lin N u ir 1995 ;62 (su pp l):2 50S -6 3S . P rin ted in U SA . 1995 Am e ric an S ociety for C lin ical N utr itio n

D ie ta ry suga rs and lip id m e tabo lism in ,2Keith N F rayn and Susan M K ingm an

AB STRACT W hen large am oun ts o f suga rs a re in c lud ed inthe d iets o f h um ans and other an im als , a ltera tion s in con cen tra tio nsof p lasm a lip id co nstituen ts m ay be observed : u sua lly e leva tion oftn iacy lg lyce ro l c on cen trat ion s an d som etim e s elev ation o f low -densi ty - lipo pro tein choleste ro l an d depre ssio n o f h igh-den sity -lip opro te in cho les tero l. The se e ffec ts are n o t se en w ith am oun ts ofsu gars ty p ic al o f tho se in the W estern d iet, a l tho ugh m o re infor-m ation is needed on postp ran d ial triacy lg lycero l concen tra tio ns,w hich m ay b e affec ted m ore read ily th an fasting concen tra tio ns.T he e leva tion o f tn iacy lg lycero l co ncen tration s ap pears to re flec tbo th in cre ased hepat ic very-low -density -l ipo pro tein tr iacy lg lyc-e ro l se cre tion an d im pa ired cle arance . Som e peop le a re m orere spo nsive to these effe cts of d ieta ry su ga rs than a re o th ers . Per -haps su rp rising ly , in m any stud ies p eo ple w ith d iabete s m ell itus ,e ithe r in su lin dep en den t or n on- insu lin d ependent, s eem to bep ro tected from alterations in p lasm a lip id concen tra tio ns brough tabou t by la rge am ounts o f d ie ta ry sugars. Am J C lin N u trl995 ;62(suppl) :250S-63S.

KEY W ORDS D iabe tes m ellitu s, fru ctose , g lu co se , lip idm etabo lism , p lasm a cho les te ro l, p lasm a tn iacy lg lycero l,suc rose

I NTRODUCT IONThe eleva tion o f b loo d lip id concen tra tions in response to

la rge am ounts o f d ie ta ry sugars , pa rticu la rly fruc tose and su-c rose , has been recogn ized fo r > 30 y [early re fe rences areg iv en in (1 )]. C onsum ption of these sugars h as been assoc ia tedw ith inc reased p lasm a tn iacy lg lycero l con cen tra tions in p ar tic -u la r, bu t changes in p lasm a cho leste ro l con cen tra tions havea lso been observ ed . M any stud ies in an im als and hum ans havebeen carr ied ou t to exam ine th is e ffec t, and these have beenrev iew ed ex tensive ly (2 -7 ).

M any of the ob serva tiona l stud ies in th is fie ld da te from th e1960 s an d 1970s an d rela tive ly few have been carried o u t since th epos ition w as summ arized by th e Food and D rug Adm in is tra tio nS ugars T ask Force in 1986 (4 ). H ow ever, since then severa lstud ies in re la ted a r eas hav e am plified these find ing s. In particu la r,co nside rab le em phasis has been p laced on the ro le o f sucrose o rfruc tose in the d ie t o f peop le w ith d iabe tes m ellitu s. Som e furthe rfind ings sugges t tha t o th er com ponen ts o f the d ie t, e spec ia lly fa tco n ten t, p lay a p art in m odu la ting th e effec t o f d ie ta ry sugars . T hem ech an ism s underly ing the triacy lg lycero l-rais ing effect o f fruc -to se o r sucro se hav e no t been c la rified in de ta il, a lthou gh som estud ies have add ressed ch anges in hepa tic en zym e activ ity w ithsuch d ie ts and o thers have p laced the effec t w ith in the genera l

con tex t o f po stp rand ia l m etabo lism , an area of active in te res tregard ing card iovascu la r risk .

W e first summ arize the resu lts o f o bserv ation al stud ies con -ce rn ing the effec ts o f su gars on b lo od lip id con cen trations andth en assess d ev elopm ents in th is fie ld in the m ain areas de-scn ib ed above , co ncen trating on lite ra tu re p ub lished since1986 .

SUGARS AND PLASM A TR IACYLGLYCEROLCONCENTRATIONS

The effec ts o f sug ars on fas tin g p lasm a triacy lg ly cero l con -cen tra tion s in h um ans m ust be cons ide red w ith in the con tex t o fthe m any o th er in fluences on triacy lg ly cero l m etabo lism . T h em ost im po rtan t causes o f ra ised fas ting p lasm a tn iacy lg lyceno lconcen tra tions a re ob es ity and excess ive a lcoho l con sum p tion ;gene tic abno rm alitie s and rena l fa ilu re a re less comm on fac-tons . A high -ca rbohydra te d ie t ( 55 % o f energy as can bohy -d ra te ) m ay a lso ra ise fas ting p lasm a tn iacy lg lyceno l concen tra -tions , pa rticu la rly in th e sh ort te rm . Increased phy sica l ac tiv ityand co nsum ptio n o f n - 3 po lyun sa tu ra ted fa ts a re assoc ia tedw ith reduc tions in p lasm a tn iacy lg lycero l. G iv en the m anyfac to rs tha t m ay confo und s tud ies o f d ie t an d p lasm a tn iacy l-g lycero l concen tra tions , inc lud in g ch an ges in body w eigh t andcho ice o f sam pling tim es, it is pe rhaps no t su rp ris in g tha t thebo dy of literatu re desc rib in g the effec ts o f d ie ta ry su gars (su -c rose and fruc tose) o n p lasm a tn iacy lg lycero l concen tra tio nscon ta ins conf lic ting find ings . T h is is particu la rly so w hen testd ie ts h ave con ta ined > 20% o f energ y from sucrose and > 5%of en ergy from fruc tose , w hich is m ore th an is usua l in W este rnd ie ts. Su ch d ie ts ap pear to eleva te p lasm a triacy lg lycero l co n-cen tra tio ns in som e cases (8 -13) bu t n o t in o th ers (14 , 15). Incon tras t, the re is very little ev iden ce tha t sucrose and fru ctoseconsum ed in am ounts ty p ica l o f W estern d ie ts in f lu en cep lasm a tn iacy lg lyceno l co ncen trations (7 , 1 6-18) .

N everthe less , it is c lea r from severa l stud ies in hum an sub-jec ts tha t d ie ts con ta in ing abno rm ally h igh am ounts o f sucroseand fruc to se m ay , under ce rta in c ircum stances , lead to h ypen-tn iacy lg lycero lem ia (8 -1 3). T o som e ex ten t the e ffec t seem s tob e dose depend en t. Fo r exam ple , R e ise r e t al (9 ) show ed tha tinc reasing propo rtio ns of sucrose (2% , 15% , and 30% energy)in a con tro lled d ie t co n tain ing 44% o f energy as carbo hydra te

1 F rom the O x ford L ip id M etab o lism G roup , She ikh Ra sh id Laborato ry ,R adc liffe Infirm a ry , O x ford , UK .2 A dd res s rep rin t req ues ts to KN F ray n , O xfo rd L ip id M e tabo lism

G roup , Sh eik h R ash id Laborato ry , R adcl iffe Inf irm ary , O xford OX 2 6H E ,U K .


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SUGARS AND LIPID M ETABO LISM 25 1 Sresu lted in inc reas ing eleva tions of fas ting p lasm a triacy lg lyc -eno l concen tra tions in no rm al m en . S im ila rly , H allfn isch e t a l( 1 1) d em ons tra ted th a t in creas ing am ounts o f fruc tose (0% ,7 .5% , and 15% of energy) in a d ie t con ta in ing 43% of en ergyas carbohydra te led to propo rtio na l in creases in p lasm a tn iacy l-g lycero l in h ypen insu lin em ic su b jects . H ow ever, in the firs tstudy , th e ef fect w as no t seen in fem ale su b jec ts an d in th esecond study norm al su b jec ts w ere un affec ted by th e d ie tarym an ipu la tion ; the re fo re , dose is no t the so le de te rm inan t o fresponse .

D ie ta ry facto rs tha t m ay in f lu en ce the effec ts o f sucrose andfruc tose on p lasm a triacy lg lycero l concen tra tions in clud e th e typ eof fa t con sum ed (sa tu ra ted or po ly unsatu rated ) (19-22 ), the p ro -portion o f to ta l ca rb ohydrate in the d ie t, an d the d ie ta ry fibe rcon ten t o f the d ie t (1 8). In add ition , som e of th e d isc repanc iesbe tw een stud ies m ay be exp la ined by the u se of su b jects w ithd iffe ren t sensitiv ities to sucrose - o r fru cto se -induced hypertriacy l-g lyceno lem ia. Su b jec ts show n to respo nd m o re read ily to d ie ta rysug ars in clud e e ld er ly su b jec ts , seden ta ry sub jec ts, those w ithestab lished coro nary arte ry d isease (1 3), m ales (9 ), and hyperin -su linem ic or carbohydra te-sens itive sub jec ts (9 , 1 1). T here isa lso som e ev idence to sug gest tha t the e ffec t is m o re pro nouncedin sub jec ts w ith in itia lly e leva ted p lasm a triacy lg ly cero l con cen-tra tions (2 3 , 2 4) and m any stud ies have in vo lved sub jec ts w ithvarious hy perlip opro te inem ias. It is no t c lea r w he ther obes ityin flu en ces the effec t independen tly o f its assoc ia tion w ith theseo th er m etab o lic abno rm alitie s.

S tudy des ig ns th a t inc lud e m easurem en ts o f on ly fas tin gtn iacy lg lycero l concen tra tio ns m ay be inadequa te fo r descn ib -ing the effec ts o f d ie ta ry su gars. H ayfo rd e t a l (25) stud ied th em etabo lic e ffec ts o f fo rm ula d ie ts co n ta in in g very h ig ham ounts (45% and 65% of energ y) o f sucrose or corn syru p(m ain ly g lu cose). T hey found tha t a ltho ugh th e ef fects o f thesed ie ts on fasting p lasm a tn iacy lg ly cero l con cen tra tions w ere no td ifferen t, the sucrose -rich d ie ts s ig n ifican tly inc reased 24 -hin teg ra ted p lasm a triacy lg lycero l p ro file s com pared w ith thesed ie ts con ta in ing co rn syru p . T he re levance to h ea lth o f pos t-p rand ia l e ffec ts o f d ie ta ry sugars is co nside red in m ore de tailla te r in th is rev iew .

A re lev an t issue th a t has no t b een fu lly addressed ins tud ies o f su gars and lip id m etabo lism is w he ther sucrose-o n fruc to se -indu ced hypertn iacy lg lycero lem ia is tran sien t.M os t s tud ies, espec ia lly th ose in w hich d ie ts have con ta inedv ery la rge am ounts o f sug ar, have lasted on ly fo r days .E v id en ce f rom one s tudy in which fruc tose (80 g /d as asupp lem en t to a norm al d ie t) w as consum ed for 2 8 d by ty peIV hypen lip idem ic sub jec ts sug gests tha t the re m ay be a t-tenua tion o f th e hyperlip idem ic effec ts o f th is sug ar w ithtim e (10). H ow ever, the re is very little o the r in fo rm atio n o nth is im portan t aspec t.

B o th sucro se and fruc tose , g iven at abno rm ally h ig h am oun tsin the d ie t, h av e been show n to ra ise p lasm a tn iacy lg lycero lcon cen tra tions (9 , 1 1 , 13 , 26). T he tn iacy lg lycero l-ra ising effec to f sucrose h as usua lly been a ttribu ted to its con ten t o f fru ctose ;how ever, som e s tu d ies show tha t the e ffec t is g reate r w ithsucrose than w ith an eq u iva len t am oun t o f invert sugar, w h ichcon sists o f equ im olan prop ortions o f fruc tose an d g lu co se (27) .T h is is the so -called d isaccharide effect, w h ich has a lso b eend em onstra ted in rats (28).

SUGAR S AND PLA SM A CHOLE STEROLD ieta ry fruc to se

In ad d ition to its e ffec ts on p lasm a tn iacy lg ly cero l concen-tra tions , d ie ta ry fruc tose sub stitu ted fo r s tarch a t 7 .5 -20% o fenergy has been shown to lead to eleva tions in p lasm a to ta l andlow -dens ity -lip opro te in (LD L ) cho leste ro l in hea lth y n orm alsub jec ts (1 1 , 26 , 29) . O n ly on e s tu dy in norm al sub jects (16),in w hich fruc tose w as adm in iste red at 5 0-10 7 g /d (one-th ird ofeach sub jec ts hab itua l ca rb ohydrate in take) in d icated n ochang e in p lasm a cho les te ro l concen tra tions . In ano th er stud yin w hich fru ctose w as adm in iste red a t 2 g kg body F1 - d 1(= 28% of to ta l energy), p lasm a to ta l cho les te ro l decreased ;how ever, the au tho rs a ttr ib u ted th is to a red uc tio n in the in takeof d ie ta ry fa t as a resu lt o f the h igh fruc tose co nsum ptio n (13).

D ieta ry sucroseS tud ies on the effec ts o f d ie ta ry sucro se on p lasm a cho les -

te ro l concen tra tio ns in norm al sub jec ts have been m ore equ iv -oca l. Severa l au thors h av e repor ted no ch an ge in p lasm a cho-leste ro l in respo nse to sucrose , ev en w hen sucrose w as g iv en asa very h igh pro portion of th e d ie t (11-6 5% o f energ y) (15 , 16 ,25 , 30). In con trast, in o ther s tud ies, p lasm a cho les te ro l co n-cen tra tio ns w ere observed to rise in resp onse to sucrose con-sum ption w ith in a b road ran ge (18-52% o f energy) (8 , 9 , 12 ,22) and w ith som e ev idence of do se dependen cy (9 ). In tw ocom plem en ta ry s tu d ies, red uc tio n of the su b jec ts hab itua l con-sum ption of su cro se by su bstitu tion w ith g lucose (17) o r sta rch(18) led to sign if ican t reduc tions in p lasm a cho les te ro l. In thestud y by M ann e t a l (22) , d ie ta ry sucrose a t 34% o f energyra ised p lasm a cho leste ro l in norm al sub jec ts w h en the accom -pany ing d ie ta ry fa t w as sa tu ra ted bu t no t w hen it w as la rge lyunsa tu ra ted , su gges ting tha t som e of the d isc repanc ies m ay b eexp la ined by the na tu re o f the o th er com ponen ts o f the d ie t.T h is in te rac tion is d iscussed in m o re d e ta il be low .C h anges in the p ropo rtion of cho les te ro l ca rried b y thevariou s lip opro te in frac tions in resp onse to sucrose have beenlarg e ly un reported , b u t in a s tu dy of ca rbohydra te-sens itivesu b jects g iven d ie ts con ta in ing 5% , 18% , or 33% of energ y assu crose , v ery -low -dens ity - lipo pro te in (V LDL )-, LD L -, andh igh-density -lipop ro te in (HD L )-cho les te ro l frac tion s a ll in -c reased w ith inc reas in g sucrose consum ption w hereas the ra tioo f HD L to to ta l ch o les te ro l dec lin ed (9 ) . W hen to ta l p lasm acho leste ro l has risen in resp onse to d ie ta ry sucrose , it is rea -so nab le to assum e tha t the inc rem en t is p rinc ipa lly in theV LDL or LD L frac tio ns b ecause severa l s tud ies have sug -ges ted tha t HD L -cho leste ro l con cen trations a re redu ced by ah igh-sucrose d ie t (1 8 , 3 1 , 32). H ow ever, it is u ncerta in w he therth is is an independ en t e ffec t o f su cro se p er se , because HD L -cho leste ro l concen tra tio ns m ay fa ll in respon se to h ig h-ca rbo-hydrate , low -fa t d ie ts in gen eral. T h is is d iscussed m ore fu llylate r in th is rev iew .

T he summ ary presen ted abo ve ind ica tes th a t the re a re m anyconflic tin g find ing s in the lite ra tu re concern ing th e effec ts o fdietary su gars on plasm a lip id concen tra tions and these haveled to a g rea t d ea l o f co n troversy . N ev erth e less, it a lso ind ica testha t, u nder ce rta in cond itions , con sum p tio n by norm al sub jec tso f d ie ts con ta in ing a typ ically la rge p ropor tion s of sucrose orfruc tose can lead to changes in the lipopro tein pro file tha t m aybe de lete rious in re la tion to risk o f ca rd iov ascu la r d isease . F or


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[c t

1 F- i-P

I: Gcerate

252S FR A Y N A N D K I N G M A Nthi s reason, the subject has attracted an enorm ous am ount ofresearch.

PO SSIBLE M ECHAN ISM S FOR THE ELEVAT IO N O FBLOOD TR IACYLGLYCEROL CONCENTRAT IO N S BYSUGARS

M etabol ism of glucose and f ructoseA l though glucose and f ructose are sim i l ar m olecules, they are

m etabol i zed di f f erentl y w i th in the cel l and i t is thought that m anyof the physiol ogi cal consequences of f ructose consum pti on stemf rom di f f erences in the m etabol i sm of the tw o sugars at thi s stage.T he m etabol i c pathw ays by w hi ch glucose and f ructose are m e-tabol i zed are i l l ustrated in Figure 1. T he m etabol ism of bothsugars begins w i th phosphory l ati on. I n the case of gl ucose, th istakes place under the inf luence of the enzym es hex ok inase orglucok inase, w hi ch phosphory late the m olecule at carbon 6. T heresul ting glucose-6-phosphate is subsequentl y isom eni zed to f ruc-tose-6-phosphate and f urther phosphory l ated to f ructose-1,6-bi sphosphate by the enzy m e phosphof ructok i nase. T hi s i s a rate-l im i ting step of gl ycol ysi s and i s an im portant f eature of them etabol i sm of gl ucose. Fructose-1,6-bi sphosphate i s then spl i t byaldolase into tw o phosphory lated tni ose m olecules, dihydrox yac-etone phosphate and gl yceral dehyde-3-phosphate. T hese tr iosephosphates can conti nue in the gl ycol y tic pathw ay to ox idati on orl i pi d synthesi s or can be used f or gly cogen sy nthesi s v i a thegluconeogeni c pathw ay .

T he m etabol i sm of f ructose begins w i th i ts phosphory l ati onby one of tw o enzym es, hexok inase or f ructok i nase. H exok i -nase is present i n tissues throughout the body and can phos-

L # { 1 7 6 } # { 1 7 6 } C-i -P ] --PGIVcoQSn*L ]

r tL 1 f rP1

L ! m J I 2-phohogPycerate _ _ _

r

F IG URE 1 . Pathw ay s for the m etabol i sm of glucose and f ructose in thel i ver , show ing the potential f or synthesis of both gly cerol and f atty acidm oi eties of tr iacy lglycerol s f rom f ructose. D ashed arrow s show m inorpathw ays (f ructose to F-6-P) or pathw ay s not relev ant to the presentdiscussion. F, f ructose; P. phosphate; G, glucose; D H A P, dihydrox yac-etone phosphate; T CA cycl e, tri carboxy l i c acid cy cle.

phory l ate several sugars, incl uding f ructose, at carbon 6. T heproduct of the phosphory l ation of f ructose by hexok inase i sf ructose-6-phosphate, w hi ch, as an interm ediate i n the m etab-ol i sm of gl ucose, i s subsequentl y m etabol ized by the sam eroutes as descri bed f or gl ucose (see Figure 1). H ow ever, hex -ok inase has a low af f i ni ty f or f ructose com pared w i th glucoseand in practi ce f ructose is onl y m inim al l y m etabol ized in thi sw ay. Fructose i s m ainly m etabol i zed in the l i ver (and poten-ti al l y the k idneys and sm al l i ntesti ne), w hi ch possesses f ruc-tok i nase. T hi s enzy m e phosphory l ates the m olecule at thecarbon in the 1-posi tion, f orm ing f ructose- i -phosphate, a re-action that occurs rapidl y because l i ver f ructok inase activ i ty isgreater than the com bined acti v i t i es of hepatic hexok inase andglucok inase. U nl ik e f ructose-6-phosphate, f ructose-1-phos-phate i s not phosphony lated f urther to f ructose-1,6-bi sphos-phate bef ore cleavage and theref ore by passes the rate-l im i ti ngreacti on of gl ucose m etabol i sm . T hi s al low s greater f l ux off ructose through thi s m etabol i c route and increases the rapidi tyof f ructose m etabol i sm com pared w i th that of glucose.

Cleavage of f ructose-i -phosphate under the inf l uence of theenzym e f ructose-i -phosphate aldolase y iel ds tw o tnioses, onl yone of w hi ch, dihydrox yacetone phosphate, is phosphory l ated.T he other i s the unphosphory lated m olecule gly ceral dehy de,and i t i s the producti on of thi s m olecule, rather than thegl yceral dehyde-3-phosphate produced f rom the breakdow n ofgl ucose, that represents the f undam ental di f f erence betw een them etabol i sm of the tw o sugars. I n f act, gl yceral dehyde is readi l yphosphory l ated to gl yceral dehyde-3-phosphate and can enterthe gly coly ti c pathw ay in thi s f orm . K ineti c studies and studiesusing i sotopes have suggested that th i s i s the pri ncipal route f orthe subsequent m etabol i sm of the m olecule. H ow ever, i t canalso be converted to gl ycerate and phosphory lated to 2-phos-phogl ycerate to enter gly col ysi s f urther dow n the pathw ay .A l ternati vel y i t can be conv er ted to gly cerol and be used in thesy nthesi s of tni acy lgl ycenol .

U nder anaerobi c condi ti ons, the m etabol ism of gl yceral dehyde-3-phosphate v i a gly coly si s resul ts i n an accum ulati on of l acticacid; under aerobi c condi ti ons, how ever, pynuv ate is ox idi zed bythe py ruvate dehy drogenase (PD H ) com plex to produce acety lC oA , w h ich can eith er be ox idi zed f or energy v ia the tri carboxy l i cacid cy cle or used in l ipogenesi s, f or w hi ch i t i s the carbon source.Because gly ceral dehy de can be converted to gl ycerol or acety lCoA , the m etabol i sm of f ructose has the potenti al to produce boththe f atty aci d and the gl ycerol m oieti es of acy l gl ycerol s and thusto f aci l i tate tri acy lg ly cerol producti on.E ffec ts o f fruc to se o n hep a tic fa tty ac id sy n th esis

O ne route by w hi ch f ructose m ay increase blood tni acy l -g ly cerol concentrati ons i s by al teri ng the rate of f atty aci dsynthesis in the l i ver. T he ef f ects of f ructose on hepati c f attyaci d sy nthesi s w ere rev i ew ed in detai l by Z ak im (33, 34). N otethat there i s a di sti nction betw een net de novo l i pogenesi s i n thew hole body (as ev idenced by a respi ratory exchange rati o> 1 .0) and increased hepatic f atty aci d synthesi s, w hi ch m ay(i n a net sense) be counterbalanced by f at ox i dation i n otherti ssues. T he ev idence that net l i pogenesis i s not an im portantprocess in hum ans consum ing a W estern diet i s thoroughl yrev i ew ed by H i l l and Prenti ce (35). I sotopi c m easurem ents ofthe absolute rate of f atty aci d synthesis in hum ans af terconsum ption of sugars have not yet been publ i shed, except i none abstract that show s m arked stim ulation af ter f requent


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SUGARS AND LIP ID M ETABO LISM 2535

fruc tose con sum p tion (3 6). In no rm al sub jec ts g iv en an ora lfruc tose lo ad labe led w ith 13C , 50% of the fruc to se w asconverted to g lucose , bu t the rem ainder w as unaccoun ted fo r.B ecau se p lasm a tn iacy lg lycero l co ncen trations rose by 45%(whereas th ey wou ld hav e fa llen afte r o ra l g lu co se ), it w assugg es ted tha t fruc to se m ay have co n trib u ted d irec tly to tria -cy lg lycero l sy n thesis (3 7). Fur th er s tud ies on the k ine tics o ffatty ac id syn th es is in hum an s are requ ired to c la rify th is area .

T he syn thes is o f fatty ac ids f rom carbo hydra te in th e liv e ro ccu rs w h en su bstra te is ava ilab le in excess o f the requ irem en tso f en erg y p roduc tion and requ ires the ac tiva tio n o f fatty ac idsyn thesiz ing enzym es. T he ra te o f fa tty ac id syn th es is m ay beregu la ted b y the ava ilab ility o f ace ty l C oA and by ac tiva tion ofthe enzym es of the pa thw ay , particu la rly ace ty l C oA carbox -y lase . In creas ing the flux of e ithe r g lucose or fru c to se a lon g theg ly co ly tic p athw ay w ill in crease the ava ilab ility o f ace ty l C oAand thereby s tim u late fa tty ac id syn thes is . O n a lo ng-te rmb asis, fa tty ac id -syn thes izing en zym es in the live r are in ducedby h igh in flux es o f e ithe r su gar. T here fo re , a lth ough en zym einduc tion m ay con tribu te to the fruc to se -indu ced in crease infa tty ac id syn thesis, it cann o t accoun t fo r the d iffe ren tia l re -sponses to h ig h d ie tary am oun ts o f g lucose and fruc tose seenbo th in hum ans and in ex perim en tal an im als .

N everthe less, experim en ts u sing liv er slices from both ra tsand hum ans h av e shown tha t fruc to se is genera lly a be tte rsubs tra te th an g lu co se fo r fa tty acid sy n thesis (38 , 3 9), la rge lybecause of its rap id m etabo lism , w hich allow s it to p rov ideacety l C oA m olecu les to th e fatty ac id -syn thesiz ing en zym esa t a g rea te r ra te than does g lucose (33) . U n like g lucose m etab-o lism , fru ctose m etabo lism is no t res tra ined b y the lim itingac tiv ity o f phospho fruc tok inase. A dd itio na lly , how ev er, f ruc -tose m ay fac ilita te its ow n convers io n to ace ty l C oA by tw ofurthe r p ro cesses . F irs t, in ra ts fed a h igh-fru c to se d ie t, it w asshown th at fruc tose ac tiva tes PDH by inh ib iting th e ac tion o fth e enzym e PDH kin ase , w hich pho sph ory la tes and inac tiva tesPDH (40). T h is fu rthe r en courages th e m etabo lism o f fruc toseto acety l C oA . S econd , fruc tose is though t to an tag on ize th einh ib ition of PDH by fa tty ac ids p resen t in th e live r e ithe r f romde novo lipogenes is o r re leased from ad ipose tis su e (41) .In te rferen ce of fruc to se in th is feedback inh ib ition processw ou ld a llow grea te r lipogenes is from th is sugar th an w ou ld bepossib le from the m etabo lism of g lucose .E ffec ts o f f r u ctose on t r iacy igly cer ol est er i f i cat i on andV LD L secr et i on

It has b een w ide ly accep ted tha t in bo th an im als and hum ansthe m etabo lism o f la rg e am ounts o f fru ctose lead s to inc reasesin the sy n thesis o f triacy lg lycero l and its re lease in to th ep lasm a in the fo rm o f VLDL . T he ev idence supporting th isv iew was rev iew ed by V r# {225 }na nd F#{225}bry2). T o e lev ate b loo dtn iacy lg lycero l concen tra tio ns, in c reased hepa tic fa tty ac id syn -thes is m us t be accom pan ied by increases in triacy lg lycero les ten ifica tion and V LDL secre tio n and there is ev idence tosugges t tha t fruc to se a lso fac ilita tes these pro cesses . In exp er-im en ts w ith perfused rat live rs, in fusion of p hys io lo g ic con -cen tra tions of f ruc tose resu lted in a sh ift in the ba lance ofn onesten ified fa tty ac id m etabo lism in fav or o f esten ifica tionra the r th an ox id ation and caused an increase in the sec re tion oftn iacy lg lycero l. T h is e ffec t w as no t seen w ith g lucose a lone ,a lth ough in fus ion of a m ix tu re o f g lu cose and fru ctose (sim u -lating sucro se m etabo lism ) fu rthe r enhanced the effec t. F a tty

ac id este rification w as a lso favored b y in fu sion of insu lin (3 3).It w as sug gested tha t the e ffec t m igh t be m ed iated by increasesin the concen tra tion of m alon y l C oA .

T n iacy lg lycero l syn thes is is depen den t on the ava ilab ility o ffa t ty ac ids , bo th syn thes ized by the live r an d p resen t in thep lasm a as nones ten ified fa tty ac ids. P lasm a noneste rified fattyac id concen tra tions m ay b e increased by re lease o f fa tty ac idsfrom ad ipose tissue and th ere is som e ev id en ce from stud ies inra ts rece iv ing h igh -fruc tose d iets tha t f ruc tose m ay fac ilitatehepa tic tr iacy lg lycero l syn th es is by enh an cin g the release o fnones ten if ied fa tty ac ids from ad ipo se tis sue . B ecau se g lycero lre lease from ad ip ose d ep o ts is no t inc reased b y fruc to se , it isthough t tha t th e e ffec t is m ed ia ted by a reduced rate o f rees -ten if ica tion of fa tty ac ids w ith in ad ipose tis sue (42). In partic -u la r, fruc tose m ay inh ib it th e insu lin sup press ion of no nesten i-fied fa tty ac id re lease from ad ipose tissue (4 3). In th is w ayfruc tose m ay fu rthe r inc rease the ra te o f tn iacy lg lycero l syn-thesis and V LDL secre tion in to th e circu la tion . If b o th non es-ten if ied fa tty acid re lease and hepa tic es ten if ica tion of fa ttyacids are inc reased , then the po ten tia l ex is ts fo r an in creasedrecy cling of fa tty ac id s (in add ition to any increased V LDL -triacy lg lycero l secretion aris ing from de novo lipogenes is ). W eare no t aw are tha t th is has been inv es tiga ted .E ffects o f f r u ct ose on V L D L catabol ism

A ltho ugh the effec ts o f f ruc tose on V LDL secretion ap pearto be w ell es tab lished , these conc lusion s have been cha llen gedby som e s tud ies dem onstra ting an im pa irm en t o f tn iacy lg lyc -e ro l rem ova l from the circu la tion . T h is w as found in hum ans(24 , 44 ) and in an im als b u t w as m ore ex tens iv ely inv es tiga tedin the la tter : an im pa irm en t o f VLD L ca tab o lism , e ithe r inadd ition to en hanced V LDL syn thesis o r in its absence , hasbeen dem on stra ted in fruc tose - o r su crose -fed rats , bo th non -d iabe tic (4 5-47) and d iabe tic (48 , 49) . T hese stud ies sug gestth at fru ctos e feed ing m ay resu lt in red uced hydro lys is o f V LD Ltn iacy lg lycero l in periph eral tis sues as w ell as im pa ired h epa ticc learan ce of V LDL (47). T h is catabo lic defec t appears to beassoc ia ted w ith an in crease in the size an d tn iacy lg lycero lcon ten t o f VLD L partic les (50 ) and w ith a reduc tion in the ra tioo f apo lipop ro te in s E and C (51). It m igh t re flect e ith er ana lte ra tion in the na tu re o f the partic les o r a d efec t in therem ova l m ech an ism . M am o et a l (47) foun d tha t VLD L iso-la ted from fruc tose -fed ra ts w as re la tive ly resistan t to h ydro -lysis by lipopro tein lipase (LPL ) ex v iv o and a lso tha t live rsfrom fruc tose -fed ra ts sh ow ed im paired rem ova l o f V LD Ltn iacy lg ly cero l. Th e la tte r f in d ing im plies defec tive recep to r-m ed ia ted u p take of V LDL partic les, because VLDL -tn iacy l-g lycero l hyd ro lys is b y LPL o ccu rs on ly in ex trahepa tic tis sues .T here is co nflicting d irec t ev id ence from an im al s tu d ies fo r achange in LPL ac tiv ity in su crose or fru ctose feed ing . P osthe -parin p lasm a LPL activ ity (m easured ex v iv o) w as red uced (5 2 ,53) o r un affected (47) in chron ic sucro se - o r fru cto se -fed ra tso r in creased tw o- to th ree fo ld in m onkeys (54 ). A d ip ose tis sueLPL ac tiv ity is un ch an ged (48 , 5 5) o r inc reased (56 ) in su -c rose -fed ra ts . In hum ans th ere is o n ly ind irec t ev idence . Aprio r bou t o f exhaus tiv e ex erc ise n u llifie s the p lasm a tn iacy l-g lycero l-ra ising effec t o f acu te o ra l fruc to se ing es tion , p roba-b ly v ia stim ula tion of LPL ac tiv ity (57). T he c lea rance o ftn iacy lg lycero l, adm in is tered as an in traveno us lip id em uls io n ,is im p a ired d uring carb ohydrate -indu ced hypertriacy lg lycero l-em ia (24) as it is (com pared w ith the s ta rv ed s ta te ) 2 and 4 h


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2545 FRAYN AND K INGM ANafte r a s in g le m ea l con ta in ing sucrose (1 .5 g /kg) (5 8); thesefind ings prob ab ly re flec t im pa irm en t o f LPL ac tiv ity .

SUG A R S A N D L IP ID M E T A B O L I SM IN D I A B E T E SThere h as b een cons iderab le in te rest in the ro les o f d ie ta ry

su crose and fru ctose in p eo p le w ith d iab etes b ecause the g ly -cem ic respo nse to fruc tose is m uch less than tha t to an equa lam oun t o f g lu co se . T he use of fruc tose as a sw ee ten er fo rpeop le w ith d iabe tes is the re fo re an attrac tive id ea . B ecause theuse of fruc tose is la rge ly insu lin ind ependen t, the rep lacem en to f g lucose w ith fruc tose in th e d ie t m ay h elp to im proveg lycem ic con tro l. H ow ever, the chan ges observed in no nd ia -be tic sub jec ts consum ing h igh-sucrose or h igh-fruc tose d ie ts,a s d iscu ssed ab ove , a re po ten tia lly un desirab le fo r p eo p le w ithd iabe tes. T he inc idence of m acrov ascu la r d isease , inc lud inga theroscle ros is o f the coron ary vesse ls , is h ig h in d iabe tes (59)and there is ev id en ce tha t h ig h p lasm a triacy lg lycero l co ncen-tra tio ns m ay p lay a causa l ro le (60). M any peop le w ith n on-insu lin -dependen t d iabe tes m ellitu s (N IDDM ) are insu lin re -s is tan t and have the fea tu res o f in su lin resis tance assoc iatedw ith inc reased risk of coronary heart d isease, inc lud ing h yper-tn iacy lg lycero lem ia and d ep ressed HD L -cho leste ro l con cen tra -tions . B ecause th e tn iacy lg lycero l-ra ising effec ts o f d ie ta rysucrose or fruc tose m ay be (as m en tioned earlie r) re la ted toin itia l fasting tn iacy lg lycero l co ncen tration s, peop le w ith d ia -be tes m igh t be particu la rly a t risk w hen fo llow ing such a d ie t.M any stud ies have add ressed these concerns , an d on the w holethe ir resu lts have been reassu ring (T ab le 1) .

I n su lin -d ep en d en t d iab e t es m ellit u sThere have been re la tive ly few stud ies o f insu lin -dependen t

d iab e tes m ellitu s (ID DM ), perhaps because early reports (7 6)show ed no benefic ial ef fects o f fruc to se on g lycem ic con tro l insub jec ts w ith m o re sev ere d iabe tes (rev iew ed in 7 7). H ow ever,few de le te rious e ffec ts o n p lasm a tr iacy lg lycero l o r cho les te ro lconcen tra tio ns w ere found in sub jec ts w ith reason ab ly g oodg lycem ic con tro l (63 , 73 , 7 7), a lthough B an tle e t a l (73 ) founda rise in se rum LDL -cho les te ro l con cen trations a fte r 4 w k o f ad ie t in w h ich 2 0% of th e energy cam e from fru ctose (LD L -cho leste ro l concen tra tio ns w ere 2 .46 com pared w ith 2 .08mm ol/L w ith the con tro l d iet). Pe rro tti e t a l (78 ) stud ied sixpa tien ts w ith IDDM who w ere consum ing a h igh-ca rb ohydrated ie t (60% o f energy from carbohydra te com pared w ith 41% inthe con tro l d ie t, bu t w ith id en tica l s im ple sugar in takes) fo r10 d an d found no effec ts o f d ie t on fas tin g lip id co ncen tration s(und er co nd itio ns tha t, a s rev iew ed be low , m igh t have led tohyp er tn iacy lg lyceno lem ia in nond iabe tic sub jects p red isp osedto su ch an effec t).

N on -in su lin -d ep en d en t d iab e t es m ellit u sA s for ID DM , th e f in d ings co ncern ing the e leva tion of

p lasm a tn iacy lg lycero l and cho les te ro l concen tra tio ns are gen-e ra lly reassu ring in tria ls o f long -te rm feed ing o f fruc tose- o rsu crose -en riched d ie ts to peop le w ith N IDDM ( see Tab le i),even in tria ls u sing la rge am ounts o f th e su gar (eg , 2 20 g /d ). Inan in te res tin g a lte rn a tive ap proach , G allagher e t a l (79 ) fo l-low ed 5 1 m ale pa tien ts w ith N IDDM who w ere ass igned tod iffe rin g d ie tary trea tm en ts fo r 4 y . S im ple sug ar in take w asno t reported , bu t sub jec ts w ith low er in takes of to ta l ca rboh y-

d ra te had h igh er fas ting p lasm a triacy lg ly cero l co ncen tra tion sthan d id o th ers. T h us aga in , the expec ted adv erse e ffec t o fh igh-ca rb ohydrate in take on triacy lg lyceno lem ia w as no tobserved .

D esp ite the genera l favo rab len ess o f the find ings lis ted inT ab le 1 , H ollenbeck e t a l (80 ) adv ise cau tion in the p resc rip tionof h igh-sucrose d ie ts fo r p eo p le w ith N IDDM , sugges ting tha tlong- te rm effec ts, inc lud ing e leva tion of p lasm a tn iacy lg ly cen o lconcen tra tio ns and depression of HDL cho les te ro l, have n o t ye tbeen thorou gh ly exp lo red and tha t w e are no t y et ab le to pred ic tin w hich ind iv idu als adverse ch an ges m ig h t occur. A ltho ugh itm ay b e true tha t d e ta ils o f each o f the stud ies can be critic ized ,the near unan im ity of fin d ing a lack of e leva tion of p lasm atriacy lg lycero l concen tra tion s an d m ostly a lack of e ffec t oncho les te ro l co ncen tra tion s in resp onse to fru ctose - o r sucrose -en riched d ie ts in su b jec ts w ith d iabe tes is in m arked con trastw ith the f in d ings in nond iab etic sub jec ts . T h is p rom pts thequ estion as to w hy there sho u ld be such a d istinc tion .

O n e poss ib ility is tha t p eo p le w ith d iab etes a lready d isp laythe ad verse e ffec ts tha t m igh t be assoc iated w ith sug ar con -sum ption (particu la rly h ypertn iacy lg lycero lem ia) and have nofu rthe r capac ity fo r response . T h is sug gestion is no t b orne ou t,how ever, by the s tu d ies lis ted in Tab le 1 . In these stud ies , theco n tro l p lasm a tn iacy lg lycero l concen tra tio ns range from low -n orm al [eg , the IDDM subjec ts o f B an tle e t a l (73): m ean 0 .72m m ol/L ] to h igh [eg , 3 .3 1 mm ol/L fo r su b jec ts o f A nderson e ta l (70)]; in any case , the f in d ings in n orm al sub jec ts sugg es tth at the grea te r the in itia l tn iacy lg lycero l concen tra tion , thegrea ter th e response to sugar con sum p tion .

A n alte rna tive su ggestion m igh t be th a t peo p le w ith d iabe tesd isp lay an ex ag gera ted imm edia te insu lin respon se to su gar( fruc tose or sucrose) consum ption com pared w ith th at in non-d iabe tic peop le . A lthough fru c to se in gestion does n o t ra ise thep lasm a g lucose concen tra tio n to th e sam e ex ten t as does g lu -cose , the re is, in sub jec ts w ith N IDDM , an imm edia te insu linrespo nse to an o ra l fru c to se load even w ith re la tive ly sm alldoses [eg , 15-50 g (8 1)]. T h is is n o t seen in no nd iabe ticsub jec ts (82 ), p erhaps because th e insu lino trop ic e ffec t o f fru c -tose is s trong ly dependen t o n th e in itia l p lasm a g lucose co n-cen tration (83); thus , peop le w ith e leva ted p lasm a g lu co seconcen tra tio ns m ay d isp lay a po ten tia tin g effec t. T he acu tesup press ive effec t o f in su lin (a t leas t in cu ltu red hepa to cy tes )on VLDL -tn iacy lg lycero l secre tion (8 4 , 85) co u ld perhap s ac-coun t fo r the lack of e lev ation of tn iacy lg lycero l con cen tra tionin peop le w ith h igh fasting p lasm a g lucose concen tra tions .H ow ever, the re a re p rob lem s w ith th is hypo thes is. C hron ice leva tion o f in su lin con cen tra tions m ay have oppos ite e ffec ts(ie , ch ron ic stim ula tio n of V LDL -tn iacy lg lycero l sec re tion ),and th is h ypo thes is cann o t exp la in the pro tec tion ag ains t sugar-induced hypertn iacy lg lycero lem ia seen in peop le w ith IDDMw ho are unab le to m oun t an acu te insu lin respo nse to sugaringes t ion .

I N T E R A C T IO N S B E T W E E N S UG A R S A N D DW T A R YFA T

It has lo ng b een know n tha t the na tu re o f d ie ta ry fa t in flu -ences the lipopro te in pro file . Sa tu ra ted fa tty ac ids tend toinc rease se rum to ta l cho les te ro l concen tra tio ns com pared w ithunsatu rated fa tty acids ; n -3 u nsa tu ra ted fatty ac ids a lso ten d to


6/14

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Ruderm an e t a l, 1 97 1(89)

M ancin i et a !, 19 73 (24)

No rma l (n = 5 M );hyper tr iacy lg lycero lemic(n = 4 ? M )

No rma l (n = 4 F , 12 M )

8 d (n orm al) , 14 d(pat ien ts)

1 0-7 0 d

7d

N ot sta ted

10 d

15 d

15 d

Couls ton e t at, 1 98 3(93)

L iu et at, 19 83 (94)

L iu et at, 1 984 (95 )

U tlm ann et a t, 19 91( 9 6 )

Hyper tr iacy lg lycero lemic(n 4 F , 4 M )

Hyper tr iacy lg lycero lemic(n 6 F, 4 M)

M i ld ly h yp er li pi de m ic(n 2 F , 6 M )

1 TG , t r iacy lg lycero l .2 Ca rbo hyd rate (CHO ) and fat pe rcen tages are p erc en t o f en erg y in take .-I G ives re ferenc es to ear lier w ork .

2565 FRAYN AND K INGM AN

4 Abstra ct o n ly .

red uce the tn iacy lg ly cero l concen tra tion . M oreo ver, the typ e o ffa t m ay in te rac t w ith the sugar com pos ition of the d iet. Inn orm al sub jec ts fed a d ie t con ta in ing 34% of energy as sucro sefo r 2 wk , se rum tn iacy lg lycero l and ch o leste ro l co ncen tra tion sw ere h igher if the fat com ponen t (30% of energy) w as m ain lysa tu ra ted fa tty ac ids th an if it w as po lyun sa tu ra ted fa tty ac ids(22). In p a tien ts w ith various h yperlipopro te inem ias, even ad iet w ith th e very h ig h con ten t o f 40% of energ y as sucro se(com pared w ith sta rch ) d id n o t ra ise p lasm a tn iacy lg lycero l andch o leste ro l concen tra tions if the fa t com ponen t o f the d ie t w asm ain ly po lyu nsa tu ra ted fa tty ac ids . If th e fa t com pon en t w assa tu ra ted fa tty ac ids, these concen tra tions in creased (19-21).M ore recen tly these in te rac tio ns have b een s tu d ied in an im als.Som e resu lts ag ree w ith those from hum an s tud ies (54 , 86) bu to the rs a re incons isten t (87 , 8 8).

T A B L E 2E ffects o f h igh -ca rbo hyd rate d iets o n plasm a lip id concen trations

E FFE C T S O F H IG H -C A R B O H Y D R A T E D IE T S

A lthou gh m ost o f th is rev iew concerns the effec ts o fd ie ta ry su crose and fru cto se , the re is a w iden issu e concern -ing th e prop ortion o f energy in the d ie t supp lied by carbo-hy dra te. It h as been recogn ized since th e 1950s tha t ah igh -carbohydra te d ie t m ay eleva te p lasm a triacy lg lycero lcon cen trations [ea rly re fe rences a re g iven in (89)]. T herehas been consid erab le em phas is recen tly on reduc ing the fa tcon ten t o f the W este rn d ie t, bo th as a m eans of reduc ing risko f coro nary h ear t d isease (C HD ) and as a m ean s of reduc ingaverag e en ergy in tak e (90). T he qu es tion then arises as tow h eth er a low -fa t d ie t, w h ich is necessa rily re la tiv ely h ighin carbo hydra te , m ay itse lf lead to adverse ch anges in b lo odl ip ids .

A uth ors Subje cts D ie t2 D u ration M ain f in d in gs

G insb erg et at , 1 97 6(91)

M elish et al, 1 977 (9 2)

R ange of TGconcen trat ions(n = 3 F , 24 M )

T yp e IVhyperlipoproteinemia(n 3)

No rma l (n = 6 F, 5 M )

F at 1% (to tal en erg yno t con tro lled , now eig h t change )

Fa t 4% (to talen erg y n otco n tro lle d , n ow eig ht ch ang e);fru cto se 1 1% o fCHO (-5 0-60 g /d )

55 % CHO , 30% fat v s40% CHO , 45% fa t;su cro se 24% ofto tal CHO fo r e achdiet

75 % CHO , 0% fat vs45 % CHO, 40% fat

60% CHO , 21% fat v s4 0% CHO , 41% fa t;sucrose 2 2-2 5% o fto ta l CHO for eachdiet

60% CHO , 21% fat v s4 0% CHO , 41% fa t;sucrose 22-25% ofto ta l CHO for eachdiet

60% CHO , 21% fat v s4 0% CHO , 41% fa t;sucrose va ried ( seetex t)

65% CHO , 20% fa t v s45 % CHO , 40% fa t;s im p le sug ars 2 5%(test) o r 28%(con tro l) o f en erg y

10 d af ter ph as ing ino ve r 30 d; o r(par t 2 ) startedimm ed iate ly for10 d

R ise in to ta l a nd V LD L TG ; r ise inVLDL cho les tero l b u t p la sm acho les tero l u naf fec ted 3

R ise in to ta l a nd VLDL TG ; rise inVLDL cholestero l b u t p la sm achole stero l fe ll; TG rem ov al (fa tto le ran ce te st) de cre ased

F ast ing TG incre ased (ab so lu te riserela ted to in itia l TGco nce ntra tio n); cho les tero luna ffe cted ; g lu cose to le ran ceunaf fected

F ast ing V LD L TG concen trationinc reased ; TG syn thet ic rateincreased4

F ast ing an d po stprand ial TGinc reased ; to ta l ch o le stero lun affe cte d bu t HDL cholestero lfell

F ast ing and po stprand ial TGinc reased (par ticu lar ly V LD LTG ) ; cholestero l an d subfrac tio nsunaf fected

F ast ing TG (to tal and V LD L)inc rea sed , bu t les s so if sucrosein take held co nstan t ; to ta lch o le stero l un affe cte d ; H DLcholeste ro l fe ll sligh t ly o n ly ifsu cro se in tak e inc rea sed

F as ting TG (to tal an d V LD L)un changed w hen hig h-CHOphased in ; to ta l, LDL , and HD Lcholeste ro l fe ll . W hen no tpha sed in , fas tin g to tal an dVLDL TG rose


8/14

E? 9 J G A R S

. I M P A R

SU GA RS A N D L IPI D M ET A B O L I SM 2575R epresentati ve studies are l i sted in T able 2. T he resul ts of al l

show ed a ri se i n f asting plasm a tri acy lg ly cerol concentrati ons,m ainl y ref lecti ng an increase in V L D L - tniacy l gl ycenol concen-trati on, af ter consum pti on of a l ow -f at, hi gh-carbohydrate diet( 55% of energy f rom carbohydrate). Som e adaptation to thi sdiet has been noted, w i th plasm a concentrati ons f al l i ng af ter2-6 w k (24, 97, 98). T otal pl asm a cholesterol concentrati onsare general l y unaf f ected or m ay even f al l because increases inV L D L cholesterol are of f set by a f al l i n L D L cholesterol (and,i n som e studies, a sm al l f al l i n H D L cholesterol ) . These f i nd-i ngs seem independent of w hether the diets w ere unusualf orm ula diets, as i n m ost of the earl ier studies, or w ere based ontypical f oods, as i n the later studies. T he resul ts have led som eauthors to adv i se cauti on in the w idespread adopti on of l ow -f atdiets (93).

H ow ever, an unresol ved i ssue concerns the role of sucrose orf ructose in producing the changes observed. T he earl i er studies,w i th f orm ula diets, w ere supplem ented w i th sof t dri nk s andinv ol ved at l east m oderate intakes of f ructose [ eg, =50-60 g/d(24)] . I n m ost of the later studies, ori gi nating f rom the group atStanf ord U ni versi ty , the sucrose content w as a f ix ed proportionof the total carbohydrate i ntake and theref ore i ncreased w i ththe high-carbohydrate diets. I n the study by L iu et al (95) tw odi f f erent m anipulati ons w ere used; one group m aintained aconstant sucrose intake (13% of total energy ) w hen theychanged f rom the low - to high-carbohydrate diet, the othergroup rai sed thei r sucrose intake (f rom 9% to 15% of totalenergy ). T he ef f ects (on f asti ng tri acy lg ly cenol and H D L -cho-l estenol concentrati ons) w ere m inim ized in the constant-sucrose group. T hus, the ef f ects of a high-carbohydrate, l ow -f atdi et on plasm a l i pi d concentrati ons m ay be m ediated in part byi ncreased sucrose or f ructose intak e. I ndeed, Coul ston et al (93)noted that the deleteri ous ef f ects w ould be el im inated i f sub-j ects consum ed carbohydrate diets com posed alm ost enti rely ofl egum es, w i thout substanti al am ounts of sucrose. H ow ever,th is possibl y exaggerates the posi ti on because there i s no hardev idence that i ncreased consum pti on of any high-starch dietw ould l ead to adverse changes unless accom panied by ahigh-sucrose intak e.

B L O O D T R I A C Y L G L Y C E R O L C O N C E N T R A T IO N S ,PO S T PR A N D I A L FA T M E T A B O L I SM , A N D R I S K O FC H DE lev a t ed t r ia cy lg ly cer o l con cen t r a t ion s as a r isk f a c t orf o r C H D

T he ev idence rev iew ed in the prev ious secti ons leads to theconclusi on that, i n som e persons, aty pi cal l y hi gh am ounts ofcertai n sugars, parti cul arl y f ructose and sucrose, i n the diet m aylead to elevati on of plasm a tniacy l gl ycerol concentrati ons.W hether hypertni acy l gl ycerol em ia i tsel f i s a ri sk f actor f orCH D is som ew hat controversi al . I n sev eral epidem iologi c stud-ies, f asti ng plasm a tniacy l gl ycerol concentrations are strongl yassociated w i th the ri sk or ex i stence of CH D but do not em ergeas independent predi ctors i n m ul ti vaniate analy si s (rev i ew ed in99). H ow ever, thi s ref l ects at least i n part a stati sti cal qui rk :because f asti ng plasm a tniacy l gl ycerol concentrati ons show ahigh degree of bi ol ogical vari abi l i ty (f rom day to day w i thi none indi v i dual , as w el l as betw een indiv iduals), the concentra-tions w i l l not em erge as independent ri sk f actors i n the

presence of som e other l ess vari able f actor w i th w hi ch they areassociated. Thi s f actor i s the H D L -cholesterol concentrati on.T here i s an inverse rel ati on betw een plasm a H D L -cholesteroland tri acy lg ly cerol concentrati ons across any populati on ofsubjects, w i th the f orm er show ing considerabl y l ess biol ogi calvari ation (w i th in one indi v i dual ). T hus, the apparent protecti veef f ect of a high H D L -cholesterol concentrati on against CH Dm ay in f act be explained (at l east i n part) by the f act that H D Lcholesterol is a m arker f or som e aspect of tn iacy l gl ycerolm etabol i sm . D espi te the f ai lure of som e studies to i denti f y thef asti ng plasm a tniacy l gl y cerol concentrati on as an independentri sk m arker, i n other studies i t does appear as such, al thoughsom etim es onl y in speci f i c groups [ eg, i n el derl y people or i npeople w i th l ow H D L -cholesterol concentrati ons (100-102)] .

T he l inks betw een plasm a tniacy lg ly cerol and H D L -choles-terol concentrations and r isk of CH D m ay be related to aspectsof postpnandial f at m etabol i sm ; the integrated tni acy lg ly cerolresponse to a f at l oad is a better m arker of C H D than i s thef asti ng tni acy lg ly cerol concentrati on (103, 104). A bri ef over-v i ew of the current understanding of tn iacy l gl ycerol and H D L -cholesterol m etabol i sm in the postprandial peri od i s giv en inF igu r e 2 .

FIG U RE 2. Postprandi al l i p id m etabol i sm and potent ial poi nts of acti onof dietary sugars. D ietary f at enters the ci rculati on as chy lom icron tri acy l -gl ycerol (T G ). Endogenous T G i s secreted f rom the l i ver as v ery -low -densi ty l ipoprotein (V L D L ). I n the postprandial period, these par ti cl escompete for clearance by l i poprotein l ipase (L PL ) in peripheral ti ssues,especial l y adi pose t i ssue. T he consequent ri se in concentrat ion of V L D LT G i s m i nim ized by suppression by insul in of i ts secretion. I nsul in al sosuppresses the release of nonesteri f ied fatty acids (N EFA s) f rom adiposeti ssue; w hich reinforces the suppressi on of V L D L T G . Insul in acti vatesadipose ti ssue L PL in the postprandial period. D uring L PL action, ex cesssurface components i ncludi ng f ree (unesteri f i ed) chol esterol (FC) m ov e toother l i poprotein species such as high-densi ty l ipoprotei n (H D L ) . T helonger the T G-r ich l ipoproteins (chy lom icrons and V L D L ) are in theci rculat ion, the greater the opportuni ty for neutral l i p id ex change w i th otherl ipoprotein speci es, i ncl udi ng H D L ; T G w i l l move into H D L in ex changefor chol estery l ester (CE). D ietary sugars m ay ex acerbate the ef fects ofinsul i n resistance. T hus, the residence of the T G -ri ch l ipoproteins in theci rculat ion i s prolonged, leading di rectl y to hypertr iacy lgl ycerol em ia andpotential l y to depression of H DL -chol esterol concentrati ons.


9/14

2585 FRAYN AND K INGM ANThe ep id em io lo g ic ev idence does no t d irec tly address th e

q uestion o f w h ether e leva ted triacy lg ly cero l con cen tra tions orthe con com itan tly decreased HDL -cho les te ro l concen tra tionsa re causa tive ly assoc iated w ith CHD . Th ere is a bo dy of b elie ftha t the tn iacy lg ly cero l-n ich lip opro te ins and th eir rem nan tsm ay be d irec tly a th e rogen ic , pa rticu la rly in the pos tp rand ia lp erio d . T h is w as firs t c lea rly sta ted by Z ilve rsm it (1 05). T heh ypo thes is is tha t these particles m ay be in te rna lized by m ac-ro phages in the arte ria l w a ll, m u ch as is thou gh t to occur w ithLD L partic les (particu la rly ox id ized LD L) . It sho u ld be re -m em bered in th is con tex t tha t a chy lom icro n con ta ins -30tim es as m any m olecu les o f cho les tero l as does a typ ical LD Lpartic le (60 000 com pared w ith 20 00 , respec tive ly ). A lth oughthe ev idence fo r th is v iew com es in part from th e o bserv edassoc ia tio n be tw een CHD and rem nan t accum u la tion in type IIIh yperlipopro te inem ia , m echan is tic s tu d ies h av e a lso confirm edthese f in d ings (103 ; rev iew ed in 106).

E leva ted fasting and postp ran d ial tn iacy lg lycero l concen tra -tions are also asso cia ted w ith inc reased ac tiva tion o f coagu la -tion fac to r V II, an im portan t risk fac to r fo r CHD (107). H ow -even , fac to r V II coagu lan t ac tiv ity h as so fa r been assoc iatedm ain ly w ith hab itua l fa t in tak e and is inc reased exp er im en ta llyby feed in g m ea ls con ta in in g la rge am ounts o f fa t (rev iew ed in108) .

T h e r o le o f in su lin r es ist an ceThe de le te rious changes in p ostp ran d ial m etab o lism seen in

m any ind iv idu a ls at risk fo r CHD m ay be tied tog e th er by th econ cep t o f insu lin res is tan ce (o r d im in ished sensitiv ity to in -su lin ). R eav en (109 ) f irs t p ro posed a w idesp read ro le fo r insu -lin res istance in comm on diseases (inc lud ing CHD ) in 1 988 . Inre la tion to the ou tline o f po stp rand ia l lipop ro te in m etabo lismg iv en in F igure 2 , in su lin resis tance cou ld be seen to affec tsevera l s tep s (rev iew ed in 110 ). Im p aired ac tiva tion o f ad ipo setissue LPL in insu lin resis tan ce m ay be exacerba ted by a failu reo f su ppress ion o f hepa tic V LD L -tr iacy lg lyceno l sec re tio n in th ep ostp rand ia l pe riod . In su lin resis tan ce a lso affec ts th e m ob ili-za tion of nones ten ified fa tty ac id s from ad ip ose tis sue ; th isp rocess is norm ally com ple te ly sup pressed by insu lin a fte r am ea l, bu t su ppression is less com ple te in insu lin res istance(1 1 1). Inc reased d e live ry o f n onesten ified fa tty ac ids to th elive r is like ly to augm en t VLD L -tn iacy lg lycero l sec re tion fu r-then . B ecause of a low er ac tiv ity o f LPL in the p ostp ran d ia lp erio d , the re w ill be less ac tiv e transfe r o f cho les tero l in to th eHD L pool an d m o re ac tiv e lo ss o f HDL cho les tero l v ia lip idexchang e m ediated b y cho les te ry l-es te r transfe r p ro te in . Inadd ition , ch ron ic h ypen insu linem ia m ay have fu rthe r adv ersee ffec ts in insu lin resistance such as d irec t s tim u la tion of a rte rialsm ooth m u sc le p ro life ra tion and aggrav ation of the a therogen icp rocess . T h us, the re a re in tim ate links in insu lin res istancebe tw een hyp er tn iacy lg lycero lem ia , dep ressed HD L -cho leste ro lcon cen tra tion , an d CHD risk .

D ie ta ry sugars and pos tp rand ia l lip id m e ta b o l ismSug ar co nsum ptio n m igh t aggrava te these p rocesses a t sev -

e ra l po in ts , bo th in the short and in the long te rm (see F igure 2) .T ha t d ie tary sugars m ay have a spec ific e ffec t on pos tp rand ia llipem ia is sh own by stu d ies in n orm al sub jec ts, in w hicho vern igh t-fas ting p lasm a triacy lg lycero l concen tra tions w eren o t a ltered by sucrose - o r fru ctose -rich d ie ts , w hereas 24-h

pro file s sh ow ed cons isten t day tim e e lev ations of tn iacy lg lyc -e ro l concen tra tio ns (25 , 27 , 1 12 , 1 1 3). In these stud ies , the testm ea ls con ta ined th e sugars ty p ica l o f the d ie t, and acu te an dchro n ic e ffec ts w ere thus no t c lear ly d istingu ished . In separa tes tu d ies, acu te add ition o f fru ctose to an ora l fa t load increasedpo stp rand ia l lipem ia m arked ly (1 14).

O ne g enera l m echan ism m edia ting the long er- te rm effec ts o fsugars m ay be the in duc tion of insu lin res istance . Sev erals tu d ies, a lbe it in ra ts , show ed tha t h igh fruc tose or su croseconsum ption leads to a loss o f sens itiv ity to in su lin (53 , 115 -119). A ltho ugh th is has usua lly been dem ons tra ted in te rm s ofredu ced sens itiv ity o f g lucose m etabo lism to insu lin , such as ta te is usua lly a lso assoc ia ted w ith im p airm en ts o f lip id m e-tabo lism (rev iew ed in 1 09 , i 1 0 ). T he h ypertn iacy lg lycero lem iafou nd in m any s tud ies o f f ruc tose or sucrose feed in g m igh t th usbe a con sequ en ce of insu lin resistance . H ow ever, m o re stud iesa re needed to c lar ify such issues as w he ther th e insu lin nes is-tance induced in ro den ts by fruc to se feed ing is rela ted toob es ity . In on e stud y d ie ta ry su crose in creased p lasm a lip idconcen tra tions in co rpu len t ra ts bu t n o t in lean con tro ls (115).

M ore spec if ica lly , d ie tary sug ars m ay a lter the k ine tics o flip id m etabo lism in a w ay tha t accen tu a tes th e chang es char-ac ten is tic o f insu lin res istance . T hese w ere la rge ly summ arizedin the m echan ism s section . Am ong the m ost im portan t in term sof p ostp rand ial lip id m etab o lism are po ten tia l in creased re leaseof nones ten if ied fa tty ac ids from ad ipose tis sue (particu la rlyim pa irm en t o f the su ppression of non esten ified fa tty ac idsre lease by insu lin in the pos tpnand ia l pe riod ), stim ula tion ofhepa tic V LDL tn iacy lg lycero l sec re tion (particu lar ly fa ilu re o fsuppression by in su lin in th e pos tp rand ia l pe riod ), and im pa ir-m en t o f the ac tiva tio n of ad ip ose tissue LPL by insu lin . W esugges t tha t fu tu re stud ies add ress these a reas m ore sp ec ifi-ca l ly .

CONCLUSI ONS

In stud ies in w hich am ounts o f sug ars ty p ical o f th e W este rnd ie t a re p ro v ided , an e leva tio n o f p lasm a tn iacy lg lycero l co n-cen tra tio n is no t usu a lly o bserv ed . U nder particu la r c incum -s tan ces , d ie ts con ta in ing a ty p ically la rge am ounts o f su crose orfru ctose can in crease p lasm a tn iacy lg lycero l concen tra tions .E ffec ts on o ther p lasm a lip id co nstituen ts a re less c lea r andthere a re sev eral a reas o f uncerta in ty . I t is no t k now n to whatex ten t sugars have an effec t independ en t o f the to ta l ca rboh y-d ra te con ten t o f the d ie t. Som e sub jec ts a re m ore sens itive tothe su gars in th e d ie t than are o thers ; p red ispo sition m ay re lateto the in d iv idua ls sens itiv ity to insu lin . F urthe r resea rch in tothe lin ks be tw een in su lin sens itiv ity and th e respo nses to sugaringes tio n of spec ific aspec ts o f pos tp rand ia l lip id m etabo lismm igh t be v ery in fo rm ative . S om e o f the un cer ta in ty abou t theeffec ts o f d ie ta ry su gars re flec ts uncritica l m easurem en t o f thefas ting p lasm a triacy lg lycero l concen tra tio n , w hereas it is n owclear tha t th e po stp rand ia l tn iacy lg lycero l response is a m o rere levan t m easure and m ore cons isten tly a lte red by sugar in ges-tion . T he tim e course of th e effec ts o f d ie ta ry sugars is no tc lear . It has been sugg es ted tha t any effect on b lo od lip ids istrans ien t (pa rticu la rly in d iabe tes). R eavens g roup (7 5) hascons isten tly argued th a t su ch c laim s are n o t based on so lidexperim en ta l ev idence . In rea lity , th e re is no so lid exp er im en ta lev idence eithe r w ay . T h is ques tion w ill o n ly be addressed by


10/14

SUGARS AND L IP ID M ETABOL ISM 259S

fructose , dex tro se an d starch feed in g on fat-cel l lip o ly sis in n orm al

lon ger-te rm stud ies (o f a t least 1 y) o r p oss ib ly by largecase -con tro l s tu d ies . A

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9 . R eiser 5 , B ick ard M C , H allfrisch J, e t a l. B loo d lip id s and th eird istribu tio n in l ipo pro tein s in hy per insu lin em ic su b je cts fed threed iffe ren t le ve ls of suc rose. J N utr 1 98 1;1 11 :10 45-57 .

1 0 . C ybulska B , N aru szew icz M . T he e ffec t o f sh ort-te rm and pro lon gedfruc tose in tak e on VLDL -TG and rela tiv e pro per tie s on ap o C II I andapo C II in the V LD L frac tion in ty pe IV hype rlipop ro tein aem ia.N ah ru ng 1 98 2;2 6:2 53 -6 1.

1 1 . H allfris ch J , R e iser 5 , P ra the r E S . B loo d lip id d istr ibu tio n o f hyp er-in su l inem ic m en consum in g thre e le vels of fructose . A m J C lin N u tr1983;37 :740-8 .

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14 . Tu rne r JL , B ierm an EL , B run zel l JD , et a l . E ffe ct o f d ie tary fruc toseon trig lyc eride tran spo rt an d g lucoregu lato ry horm ones in hyp ertri-g lyc eridem ic m en . Am J C lin N utr 19 79 ;32 :10 43-50 .

15. B eh all KM , M ose r PB , K e lsay JL , et a l . Th e effect o f k in d ofc arb ohydrate in the d iet and use of o ral con trac ep tive s o n m etabo lismo f yo ung w om en . II S erum lip id lev els. Am J C lin N utr 198 0;3 3 :825-31 .

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17 . L ock 5 , F ord M A , B agley R , et a l. T he ef fec t o n p la sm a lip ids of th eisoen erg etic re p la cem en t o f tab le sucro se b y dried g lucose syrup(m a ize-syrup so lids ) in th e n orm al d iet o f ad u lt m en over a pe riod o f1 y ear. B r J N utr 19 80 ;43 :25 1-6 .

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1 9 . L ittle JA , B irchw ood BL , S im m ons D A , et a t. In te rre la tionsh ipbetw een th e k ind s of d ie tary ca rbo hydra te an d fa t in hy per lipo pro -te in em ic pa tie n ts. Pa rt I. S ucrose an d starch w ith po lyu nsa turated fat .A th ero scle ros is 197 0;1 1 :173 -81 .

20 . B irchw ood BL , L ittle JA , A n tar M A , et al . In ter re la tio nsh ip b etw eenthe k in ds of d ietary carb oh ydrate and fa t in hy pe rlip op ro te inem icp atien ts. P ar t 2 . Suc rose and starch w ith m ixed satura ted an dpoly un satu rated fats. A the roscle rosis 19 70;1 1 :1 83 -90 .

2 1 . A nta r M A , L ittle JA , Lu cas C , e t a l. In ter re la tio nsh ip be tw een thek in ds of d ieta ry c arb ohydrate and fat in hyp erl ipo pro tein em ic p a-tie n ts . Pa rt 3 . S yn erg istic e ffe cts o f su cro se and an im al fa t on serumlip ids . A th ero scle ros is 1 97 0;1 1 :191 -20 1 .

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1 1 4. Cohen JC , S cha ll R . R eassess ing th e ef fec ts o f s im p le carboh yd rate son th e serum trig lyc erid e resp on ses to fa t m eals. A m J C lin N utr1 98 8 ; 4 8 : 1 03 1 - 4 .

1 1 5. Bhath en a SJ , K ennedy BW , Jone s J, e t a t. E ffe ct o f d ieta ry ca rbo -hyd rates on in su lin an d glu cagon re cep tors in a n ew m ode l ofno nin su l in -dep end en t d iab etes -SH R IN -corpu ten t ra t. P roc Soc E xpBi o l Me d 1 98 9; 1 92 : 66 - 71 .

116 . G u tm an R , B as ilic o M Z , M occh iu t ti N , e t a t. D iazo xid e preven ts thedevelopm en t of h orm on al and m e tab o lic abno rm ali ties pre sen t in ra tsfed a suc rose ric h d ie t. H orm M e tab R es 1985;1 7 :4 91 -4 .

117 . Reav en GM , H o H , H offm ann BB . Som atosta tin inh ib it ion o f fru c-tose-in du ced hype rten sio n . H ype rten sio n 1 989 ;14 :1 l7-2 0 .

1 18 . Thorb urn AW , S tor lie n LH , Jen k in s A B , et at. F ru cto se-indu ced inv ivo in su l in resistan ce an d eleva ted p la sm a trig lyc erid e lev els in rats.Am J C lin N utr 1 989 ;49 :11 55 -63 .

1 19 . W rig h t DW , H ansen R I , M ondon CE , et at. Su cro se-indu ced insu linresista nce in the ra t: m odu lat ion b y ex ercise and diet . A m J C lin N utr1983;38 :879-83 .

C O M M E N T A R YS h erm an : A lt h ou gh a h igh -car b oh y d r a t e , low -f a t d ie t m a yprodu ce an a therogen ic respo nse from th e perspec tiv e of th eb lood lip id p ro file, en durance a th le tes a re adv ised to consum eas m uch carb ohyd ra te in th e ir d ie t as p oss ib le to res to re bodycarb ohydrate sto res be tw een tra in in g sess ions (1 ). N everthe -less , ex ercise tra in ing can fav orab ly a lte r the b lood lip id pro fileand prov id e rela tive pro tec tio n aga ins t ca rd iov ascu la r d iseasedesp ite the con sum p tion of a h igh-ca rbo hydrate d iet. F or ex-am ple , w e ll- tra ined run ners w ho typ ica lly con sum ed a d ie tcon ta in ing i2 .55 M J/d (300 0 kca l/d ) com prising 71% carb o-hy dra te , 15% pro tein , and 1 4% fa t had an exce llen t se rum lip idpro file [tn iacy lg lycero l, 1 .03 0 .2 4 mm o llL (91 21 m g/dL );

g lycero l, 0 .05 0 .01 mm ol/L ; fa tty acid , 0 .36 0 .04 mm ol/L ;to ta l cho les te ro l, 4 .11 0 .47 mm ol/L ( i5 9 18 m g/dL ); andh igh-d en sity -lipopro tein cho leste ro l, i.58 0 .16 mm ol/L (6 1 6 m g /dL )] (W M Sherm an , unp ub lished o bserva tions ,1980) .T hese resu lts are a lso su pported by the observa tion tha t tra inedrunn ers consum ing 10 .5 9 M J/d (25 30 kca l/d ) com pris in g 62%carbohydra te , 11% pro te in , and 27% fa t a lso h ad exce llen tb loo d lip id pro file s : 0 .99 0 .i6 mm olfL (88 14 m g/dL )tn iacy lg ly cero l, 388 0J3 mm ol/L (150 5 m g /dL ) to ta lcho les te ro l, and 1 .4 0 0 .13 mm o l/L (54 5 m g/dL ) h igh-dens ity - lipo pro te in cho les te ro l (2 ). F urthe rm o re , cond ition ingac tiv ity o f an in tensity > 6 m etabo lic un it equ iva len ts(M ET s)/w k reduces b loo d tn iacy lg lycen o l to 1 . 13-1 . I 9 m mol/L(100 -105 m g/dL ), w hereas less con d ition in g phy sica l ac tiv ity


13/14

2625 FRAYN ANDdoes no t a lter b lo od tn iacy lg lycero l (1 .33-1 .3 9 mm ol/L , o r1 18-123 m g/dL ), as found in 1675 m id d le-ag ed m en fromeaste rn F in lan d (3 ).

References1. S herm an W M . M e tabo lism of su gars and phys ical p erform an ce. Am J

C li n N u tr 1 99 5; 62 (s up pt ): 22 8S -4 lS .2. Davis P0 , B arto ti W P , D urs tine JL . E ffec ts o f acu te exe rcise in ten sityon p lasm a lip ids and ap otip op ro te ins in tra in ed- run ners. J A pp I Phys io l

1992 ;72 :914-9 .3. Lakka TA , Salonen iT . Phy sic al act iv ity and se rum lip id s: a c ros s-

se ctio na l po pulatio n s tud y in E astern F inn ish m en . Am J Ep idem io l1 99 2; 1 36 :8 08 -1 8.

K han: W hat shou ld th e averag e Am erican be ea ting in te rm s ofsim ple an d com plex carbo hydra tes? Is the re a stud y tha t d i-rec tly assesses the benefits o f com plex com pared w ith s im plecarbohyd ra tes in te rm s of long- te rm lip id m etabo lic ch an ges?Au th ors rep ly : F ew lon g-te rm stud ies hav e been reported .Som e ev idence sug gests tha t a h ig h-ca rbohydra te , h igh-fibe rd ie t w ill have benefic ia l e ffec ts on lip id concen tra tions in thelo ng te rm (1), b u t little ev iden ce ex ists tha t d istingu ishesbe tw een s im ple sugars and s ta rches.

ReferenceI . Anderson JW , G a rrity TF , W ood C L , et at. P ro spe ctiv e, rand om ized ,

con tro lled com par iso n of th e effe cts of low -fat and low -fat p lu s h ig h-f iber d iets o n serum lip id co ncen tratio ns . A m J C lin N u tr 19 92;56 :887-94 .

W olever-reply to K han: Is there a study com paring sim plev ersus com p lex carb ohydrates in term s of lo ng-te rm lip id m et-abo lic ch anges? T he an sw er to th is depends on how sim ple andcom p lex carb ohyd ra tes a re defined . Th ere a re sev eral stud ies inw hich s ta rch (com plex carboh ydra te ) w as rep laced by sucro se(s im ple carbo hydra te ). T here a re a t leas t tw o w ays by w hichth is exchange m ay affec t lip ids. O ne is by the m etab o lic e ffec tso f f ruc tose versu s g lu co

Lipid Faal Am J Clin Nutr-1995-Frayn-250S-61S

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