vasquez 1995 paper

8/14/2019 Vasquez 1995 Paper

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Am J C/in Nut r l99 5 ;6 2 :9 3-1 03 . P rin te d in U SA . 1995 Am e rican S ocie ty for C lin ical N utr itio n 93

P ro te in m e tabo lism du ring w e igh t reduc tion w ith ve ry -low -ene rgy d ie ts : e va lua tion o f th e independen t e ffec ts o fp ro te in and ca rbohyd ra te on p ro te in spa ring13Jorg e A V azq uez, U zm a K az i, and N av id M a dan i

ABSTRACT Th e a im of th is s tu dy w as to asse ss th e ind e -p enden t e ffec ts o f ca rbo hydrate and pro te in in tak es in pro te insparing during w eigh t red uc tio n . F orty -e igh t ob ese w om en w ereran dom ly ass igned to co nsum e iso energe tic (25 00 k J/d ) liqu idd ie ts tha t p rov ided the fo llow in g am ounts (g /d ) o f p ro te in andcarbohyd ra te , respec tive ly , fo r 2 8 d : 50 an d 10 , 5 0 and 76 , 70 and10 , and 70 and 86 . T h e effec ts o f ca rb ohydrate and pro te in w ereana ly zed by repea ted -m easu res an alys is o f variance (A N O VA ).C arbohydra te s ig n ifican tly af fected d aily u rina ry amm onia andto tal n itrogen ex cretion , stoo l n itrogen , and n itrogen b a lance . P ro -te in , in depen den tly o f c arb oh ydrate , sign ifican tly a ffe cte d da ilyurinary am m onia, u re a, an d to tal n itrogen ex cre tion b ut h ad n oeffec t on n itro gen b alance . C um u la tive n itrog en losses (mm ol/28d) w ere low er in the h igh -ca rb ohyd ra te g roups than in th e low -carboh ydra te g rou ps (18 69 392 an d 361 1 328 , P = 0 .003 ) bu tw ere s im ila r in the gro ups rece iv ing 50 and 70 g pro te in /d (317 1 327 an d 2326 430 , respec t ive ly , P N S ). T hese resu ltsind ica te th at ca rbo hydra te and pro te in have independen t bu t add i-tiv e p ro te in -spa rin g effects du rin g w e igh t redu ction . Am JC /in N u tr 1995;62 :93-103 .

KEY W O RD S O besity , w eigh t reduc tion , n itrog en ba l-ance, p ro te in m etab o lism , very -low -energy d ie ts

INTRODUCTION

V ery-low -energy d ie ts (V LED s) a re frequen tly used in thetrea tm en t o f severe obes ity (1 ). Th ese d ie ts a re p rov ided e ith erin liqu id or so lid fo rm and vary in energy con ten t (12 53-33 47kJ, o r 3 00-80 0 kca l/d ) and m acnonu tn ien t com position (1 , 2 ).T here a re m any con trovers ies regard in g the use of these d ie ts .Fo r ex am p le , it is s till u ncerta in w he ther it is possib le toach ieve zero or pos itive n itrogen ba lance at a ll o n these d ie ts ,w he ther fac to rs such as sex or body com pos ition in flu en ce theach ievem ent o f n itrogen b alance , an d w hat th e op tim al com -pos itio n fo r p rese rv a tion o f lean b ody m ass is (1 -3 ) .

T h e m ain o b jec tive of V LED s is to prod uce m axim al w eigh treduc tion w hile sp ar in g b ody p ro te in . H ow ever, the re is nocon sensus on the o p tim al V LED com pos itio n to ach ieve th isg oa l. In th is regard , the m ajo r a rea of d isag reem en t is there la tive am ounts o f p ro tein and carbo hydra te n eeded fo r p ro -te in sparing . O n the on e hand , the re a re V LED s tha t p rov idesm all am oun ts o f ca rboh ydra te ( 30 g /d ) an d con ta in m ostlyp ro te in (70-1 20 g /d ); on the o th er hand , the re a re V LED s tha t

p ro v ide g reate r am oun ts o f ca rbohydra te ( 7 5 g /d ) an d lesse ram oun ts o f p ro tein (3 0-70 g /d ) (3-5) .

Stud ies o f p ro te in sp ar in g dur in g w eigh t reduc tion w ithV LED s in these ex trem es h ave sh ow n conflic tin g resu lts (6 -13). F or ins tance , som e stud ies h av e show n pro te in sp ar in gw ith h ig h-p ro te in , low -carbohyd ra te (5 , 6 ) V LED s; o thers haveshow n be tte r p ro te in sparing w ith d ie ts tha t p rov ide m odera team ounts o f p ro te in bu t h igh am ounts o f ca rb ohydrate (7 ); ands till o th e rs have show n no d iffe rence at a ll (8 ). N on e th eless, there la tiv e im po rtan ce of the pro te in and carb ohydrate con ten ts inp ro te in sp ar in g is d ifficu lt to de te rm in e from these stu d ies . Forthe m ost part, p rev io us stud ies have inv estiga ted a sing leam ount o f p ro te in (7 -9 ) o r a s ing le am ount o f ca rbohydra te(1 1). W hen m ore than on e am ount o f p ro te in has been exam -ined , the V LED s w ere no t isoenerge tic (1 1 ) and d iffered ino ther asp ec ts , inc lud ing the am ount o f ca rboh ydra te (6 , 8-1 1) ,and w hen m o re than one am ount o f ca rbo hydra te has beenexam ined , the V LED s w ere n o t ison itrogenous (6 , 8 , 10 , 1 1).

T he a im of th is stud y w as to assess th e indep en den t e ffec tso f p ro te in an d carbohydra te on pro te in sparing dur in g treatm en tw ith V LED s. W e stu d ied 4 8 w om en in a m etabo lic w and w h ilethey con sum ed isoen erge tic V LED s tha t p rov id ed tw o am ountso f p ro tein (50 or 70 g /d ) and tw o am ounts o f ca rbohydra te (10on > 76 g /d ). F ifty an d 70 g pro te in /d a re con side red m arg ina lan d su rfe it am oun ts o f p ro te in , respec tive ly , dur in g w eigh tred uc tion w ith V LED s (1-4 ).

SU BJECT S AND M ETHOD SSubjec ts

Fo rty -e igh t obese w om en w ere s tud ied . E x cep t fo r ob es ity ,th ey w ere in good health as de te rm ined by h is to ry , phy sica lex am in ation , and laborato ry eva lua tion . T he study w as ap-p roved by the Ins titu tiona l R ev iew Board of the U nivers ity o fP ittsburg h and all p a tien ts gave w ritten in fo rm ed consen t.

I F rom th e C lin ica l N utritio n R esearch U nit, D ep ar tm en t o f M edic ine ,Un iversity of P ittsbu rgh S chool of M ed icine.

2 Suppo rted by gran ts D K -39157 and RR -00056 from the N ation a lIns titu tes o f H ealth . H ealth M an agem ent R eso urc es supp lied HM R 70 P lusfor th e s tud y .

3 A dd ress rep rin t reques ts to IA V azquez , M onte tlo re U nivers ityHospita l, 20 0 Lo throp S treet , P ittsburgh , PA 15213 .

Rece ived A pril 27 , 1 994 .A ccep ted fo r pub lica tio n Febru ary 27 , 1 995.


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94 V A Z QUEZ E l A LE xp er im en t a l d esign

Patien ts w ere hou sed at the C lin ical R esearch C en te r o f theU n iv e rs ity o f Pittsbu rg h M ed ical C en te r f o r 3 1 consecu tiv ed ay s. T o ensure that all p atien ts began the d ie t u nder s im ilarm e tabo lic cond ition s , patien ts con sum ed a m eat-f ree , w e ig h t-m ain tenance d ie t f o r 3 d (day s -3 to -1 ). T h is d ie t p rov ided75-100 g pro tein an d 10 4 60 -1 2 552 k J/d (2 500 -3 000 k cal/d ).O n th e fou r th d ay (d ay 0 ), p a t ien t s w er e assign ed t o consum ea V L ED that p rov ided 2 500 k J (600 k cal) and 10 g canb ohy -d rate /d on to co nsum e an iso en enge tic and ison itrogeno usV L ED th a t p r ov id ed 7 5 g car b oh y d na t e /d fo r 28 d (day s 0-28).T he f irs t 21 patien ts consum ed V L ED s that p rov id ed 50 gpn o tein /d and th e rem aind er co nsum ed V L ED s that p rov ided 70g pno te in /d . A ll d ie ts w ere pro v ided in liqu id f o rm . Patien tsw ere encou raged to consum e n onenergy -con tain in g f lu id s lib -e rally , an d ac tiv ity w as lim ited to w alk ing in the h osp ital w and .Patien ts w ere w e ighed d aily in the m o rn ing af te r v o id ing .T em peratu re , p u lse rate, an d sup ine and s tand ing b lood pres -su nes w ere m easured tw ice daily . E lec trocard iog ram s w ereperf o rm ed w eek ly . Fas tin g v eno us b lo od sam p le s w ere ob -tam ed at day s 0 , 14 , and 28 o f treatm en t f o r m easurem en ts o fp lasm a 3 -hy dro x y bu ty rate (f 3 -O HB ), non es ten if ied f ree f attyac id s (N EFA s) , in su lin , th y no x in (T 4 ), tn iiod o thy no n ine (13 ) ,e lec tro ly te s , g luco se , u ric ac id , am ino acid s , alb um in , p realbu -m m , and ne tino l-b ind ing pro te in con cen tration s . A t the en d o f28 d, th e d iet w as chang ed to so lid s that p rov ided 418 4 k J(10 00 k cal) and 100 g p no te in /d , and patien ts w ere d isch argedto con tinue d ie ting at hom e .

Die t sT h e f ou r V L ED s w ere isoenerge tic (2468 -257 3 k J/d , on

5 9 0 - 6 1 5 k cal/d ) and p rov ided e ith e r 50 or 70 g h igh -qualityp ro te in /d . T he so urces o f p ro te in w ere lac talbum in , m ilk p ro -te in , case in , an d w hey . For each am oun t o f p ro te in , th ere w asa low (10 g /d ) and a h igh (76 or 86 g /d ) carbohy d rate V L ED .For s im p lic it y , w e w ill r e fer t o t h ese V L ED s as SO P /b C ,50P/76C , 70P/1O C , and 7 0P/86C , re spec tiv e ly , w h ere P isp ro te in and C is carbohy d rate (T ab le 1 ) . T h e V L ED s a lsoprov ided s im ilar am o un ts o f sod ium , po tass ium , calc ium , phos -phoru s, m ag nesium , v itam in s, and trace e lem en ts th at m e t therecom m ended d ie tary allow ances (1 4 ). A ll d ie ts w ere on ig i-nally in pow der f o rm and w ere prepared f re sh daily by add ingd istilled w ate r. C om p liance w as m on ito red b y d irec t 24 -h ob -se rv ation o f patien ts and by daily m easurem en t o f u rinaryace toace tic ac id co ncen tration (L abs tix ; M ile s L abo rato ries ,E lk hart, IN ).

U rine co llect io nsU rin e w as co llected ev ery 24 h an d sto red w ith ou t p re se r-

v ativ e s in p lastic con tainers k ep t at 4 #{ 176} Cu rin g the co llec tion .A t th e en d of each p er iod , t h e v o lum e w as m easur ed andaliquo ts w ere p laced in tub es con tain ing 20 L 2 m o l H C 1 /L o ra f ew cry stals o f th y m o l. T he sam p le s w ere then f ro z en at-20 #{ 176} Cn til analy z ed . M enstrual period s occurred during thes tud ie s in a f ew sub jec ts. T o prev en t con tam ination w ith b loo d ,the u rine co llection s w ere d iscon tinu ed f o r 2 -4 d durin g tho seep isodes . U rine ex cre tion v alues durin g the m ens truatio n day sw ere ex trapo lated f rom th e nonm ens truation day s by usin greg re ss io n an aly sis.

TABLE 1D aily ene rgy and nutrien t in tak e s f rom the v e ry - low -en erg y die ts( V L ED s )

V LED group50P/1O C 50P/76C 70P/IO C 70P/86C

E nerg y (Id ) 24 68 2468 2 573 257 3Protein (g) 52.5 50 .0 7 0 .5 70 .0Fat (g ) 38 .0 10 .0 32 .9 3 .0C arbohy drate (g ) 10 .0 76 .0 9 .3 8 6 .0S od ium (m g) 22 30 2079 1891 189 1Potassium (m g ) 2660 2784 2008 2008C alc ium (m g) 1 984 1904 1 044 1400Phosphoru s (m g) 9 12 982 1 147 1000M agnesium (m g ) 4 91 50 8 44 2 48 0

, A ll d iets p rov ided v itam ins and trace e lem en ts to m eet o r ex ceed th edaily recom m ended die tary allow ance s (1 4). T he 5OP/1O C and 50P/76Cv ery -low -energy d ie ts (V LED 5 ) w ere prepared b y Pf rim mer/K ab i (E rlan -g en , G erm any ), th e 7 0P/1O C V LED w as prepared by Food lek (M o rrisPlain , N I), the 7OP/86C V L ED w as a m odif ied v ers ion of a com m ercialproduc t, H M R 70 Plu s (HM R, B oston ). T o m ak e the d ie ts sim ilar in energyand m inerals , HM R 70 Plu s w as supp lem en ted w ith po ly co se (25 g /d , R ossL abo rato rie s, C olum bus , O H ), N aC I (971 m g /d) , and K C I (1 148 m g/d ).S O P, S O g p ro te in /d ; bC , 10 g carb ohy drate /d ; 76C , 76 g c a rh o h y dr at e /d ;8 6C , 8 6 g c arb oh yd rate /d .

S t o o l co llec t io n an d an a ly s isS t oo l w as co llec t ed in 4 -d p o o ls an d s t o r ed a t 4 # {1 76}Cn t il t h ey

w ere h om ogen iz ed w ith d istilled w ate r. S am p le s o f the hom o-genate w ere stoned at -2 0 #{ 176} Cn til th e p oo ls w ere analy z ed f o rn itrogen . T he re su lts o f th e an aly s is w ere d iv ided by f o ur top rov ide an es tim ate o f daily stoo l n itrogen lo s se s.

T h e n itro gen con ten t o f th e d ie ts, u rine , and stoo l w erede te rm ined by a m icro -K je ldah l techn iq ue . j3 -OH B w as m ea-su red enz y m atically (1 5 ). N EFA s w ere m easured enz y m ati-cally by us in g a com m erc ial k it (W ak o C hem ical U S A , R ich -m ond , V A ). B lood urea n itrogen (B UN ) and am m on ia w erem easured sp ec trop ho tom e tn ically (S igm a C hem ical C o , S tL ou is). Prealbum in and re tino l-b in d ing pro te in w ere m easuredby rad ialim m unod if f u sion (B ehn inger D iag nos tic , S om erv ille ,N J). In su lin , 14 , an d 1 3 w ere m easured by rad io im m unoassay(IC N B iom ed icals m c , C o sta M esa, C A ). Plasm a am in o acid sw ere m easured by HPL C . A lb um in , to tal p ro te in , g lu cose , anduric acid w ere m easured at the c lin ical labo rato ries o f th eU n iv ersity o f Pittsbu rg h M ed ical C en te r. N itrog en balance(m m o l/d ) w as calcu lated as n itrog en in tak e m inus the sum o fth e 24 -h urine n itro gen p lu s s to o l n itrogen p lu s in sen sib len itrogen lo sse s (5 m g . k g . d . B ecause B UN w as no tm easured daily , n itrogen balance w as n o t co rrec ted b y thechanges in B UN poo l. L ean body m ass w as m easu red byb ioe lec trical im pedance analy sis (16 ) .

S ta t i s t ic sS tatistical analy se s w ere don e b y us in g segm en t 4V o f the

BM DP st a t is t ica l p ack age (1 7). T he data w ere analy z ed b yrepeated -m easures analy s is o f v ariance (A N OV A ) us ing thecarb ohy d rate (10 and > 7 6 g /d ) and pro tein (50 and 70 g /d )in tak es as independ en t v ariab le s. W hen s ig n if ican t (P < 0 .05 )in te rac tio n e f f ec ts w ere f ound by A N O V A , pair-w ise t testsw ere u sed to asse s s d if f e rences be tw een each o f the possib lecom parison s o f in te re st. T he P v alu es f rom these t te sts w e re


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PR O T EIN M ET A B O L IS M DU R IN G W E IG HT R EDU CFION 9 5ad ju sted upw ard to con tro l f o r th e m u ltip le com p arisons (18 ).T he relation o f n itrogen balance to p lasm a ho rm one con cen -tration s w as asse ssed b y regre s sion and corre lation analy s is.T he re su lts are p re sen ted as m ean S EM .

RESULTS

Pat i en t char acter i st i cs an d gener al ef f ect s of d i etIn itially , th e g rou ps w ere s im ilar in age , w e ig h t, bod y m ass

ind ex (B M I), an d lean bo dy m ass (T ab le 2 ). A ll f ou r V L ED sw ere w e ll-to lerated by th e patien ts . S pec if ically , d iarrhea, p o s-tu ral hy po ten sion , gou ty attack s , an d arnhy thm ias w ere n o tobserv ed du ring treatm en t w ith any o f th e V L ED s. T he on lyf requen t com p lain t w as con stipatio n . T h is occurred w ith eq ualf requency in all g rou ps and w as treated w ith stoo l so f ten ers an dlax ativ e s. W e ig h t lo s s w as s im ilar in all V L ED s. O n av erage ,th e m ean w eigh t lo s s af te r 2 8 d o f treatm en t w as 8 .4 0 .4 k g ,o r 7 .8 0 .2% o f in itial body w e igh t (T ab le 2 ).

Sub st r at es and hor m onesT he carboh y drate and pro tein in tak es had independ en t e f -f e c ts o n v ariou s p lasm a sub strates . T h e carbohy drate in tak e

af f ec ted the p lasm a OH B , g lucose, an d uric ac id con cen tra-tio n s bu t had n o e f f ec t on N EFA s , B UN , and creatin ine con -centrations (T ab le 3). T h e p lasm a J3-O H B concen t r at i on in -creased ov er tim e (P < 0 .001 ) f o r all V L ED s. B y d ay 14 ,f 3 -OHB had reached a m ax im um v alue and s tay ed at thatconcen tration un til th e end o f the stud y . H ow ev er, in the> 76C V L ED grou ps, th e O H B m ax im al concen tration re -m ain ed w ith in the ran ge observ ed in ob ese peop le af te r anov ern ig h t f as t, w hereas the lO C grou ps ex h ib ited v alu es in therange o f k eto s is seen af te r a short f ast o r h igh -p ro te in V L ED(T ab le 4) (19).

T he p lasm a g luco se concen tratio n d ecreased ov er tim e in allV L ED gr oups (T ab les 3 and 4). H owever , t h e r edu ct i on s f r omday s 0 to 14 w ere le ss p ro nounced in th e > 7 6C (1 1 -13% ) thanin the 1OC V L ED grou ps (28 -38% ) .

T he p lasm a uric ac id concen tration in creased during treat-m en t w ith all V L ED s (T ab le 3 ). In all g roups , th e h igh es tconcen tration s w ere observ ed at day 14 . T he increase s w ereles s p ro noun ced in the > 76C than in the 1O C V L ED groups .M oreov er, by day 28 the v alues had re tu rned to near o r be lowday -O con cen tration s in the > 76C V L ED gro ups, bu t rem ain ede lev ated in the IO C V L ED group s (T ab le 4 ).

T he p ro te in con ten t o f th e V L ED s d id no t af f ec t th e p lasm aO H B , NE FA , gl u cose, or cr eat i n i n e concen t r at i on s, b u t sig-n if ican tly af f ec ted th e uric ac id and B UN concen tration s (T ab le3 ). In the S O P V L ED group s, th e B UN concen tration decreasedf rom d ay s 0 to 14 and rem ained depressed at d ay 28 . Incon tras t, in the 70P V L ED gro ups, th e B UN concen trationincreased f rom day s 0 to 14 and rem ained e lev ated at day 28(T ab le 4 ). T h ese changes w ere no t due to alte ration s in k idn eyf u nc tio n becau se they occurred indepen den tly o f changes inp lasm a creatin ine concen tration s (T ab le 3 ).

N o te th at in all V L ED group s th e chan ges in sub stratecon cen tration s w ere sm all and the p lasm a con cen tration s o f allsub s trate s rem ained w ith in th e norm al range th rough ou t thep erio d o f ob serv ation .Plasm a hor mones

Ho rm ones are k now n to in f lu ence pro te in m e tab o lism and tob e altered d uring en ergy res triction . W e there f o re m easured thep lasm a concen tration s o f in su lin , T 4 , and 1 3 at d ay s 0 , 14 , an d2 8 o f treatm en t w ith each o f the f ou r V L ED s.

T he p lasm a con cen tration s o f in su lin and T 3 decreased ov ertim e durin g treatm en t w ith all V L ED s (T ab le 3 ). T h e greate rred uc tion s occurred f rom d ay s 0 to 14 . A f ter th is tim e , th ein su lin an d T 3 concen tratio n s rem ained re lativ e ly con stan t.H ow ev er, th e red uc tion s f o r bo th horm o nes w ere les s p ro -n ounced in the > 76C th an in the IO C V L ED groups .

I n com par i son w i t h 13, t he changes t hat occu r r ed i n 14con cen tration s ov er tim e w ere m odes t. E x cep t f o r the 7 0P/8 6CV L ED gr oup , t h e 14 con cen t r at i on s i n cr eased sl i gh t l y (1 .8-3 .0% ) f rom d ay s 0 to 14 f o llow ed by reduc tion s at day 28 ton ear d ay -0 concen tratio n s. 13 w as th e o n ly horm o ne th at w ass ign if ican tly af f ec ted by th e pro tein co n ten t o f th e V L ED s(T ab le 3 ) .Plasm a p r otein s

T he V L ED com pos ition m ay af f ec t th e concen tration s o fc ircu lating p lasm a pro te in s. B ecause o f the ir shorte r h alf -liv e s ,th e p lasm a co ncen tration s o f re tino l-b ind ing p ro te in and pre-album in are con sidered to be m ore sen s itiv e in dex es o f p ro te indepriv ation than are pro te in s w ith a longer half -lif e , such asalb um in . From d ay s 0 to 14 o f treatm en t, th e p lasm a concen -tration s o f re tino l-b ind ing pro tein and prealbum in decreased by2 4 -36% and rem ained low at day 28 ( Ta b le 5). A t t he sam etim es , th e re w ere also sm alle r (2 -8% ) reduc tion s in the p lasm aalb um in and to tal p ro te in co ncen tration s. T he reduc tion s in the

TABLE 2In itial p atie nt c harac te ris ti cs

V LE D gro up50P/IOC (n 10) 50P/76C (n = 1 1 ) 70P/1O C (a 14 ) 7OP /86C (n 13 )

A g e ( y )W eig ht (k g)BM I ( k g /m 2 )LBM (kg)W eight los s (k g)W eig ht los s (% )

444I 16 644250 28. 8 0.47. 5 0.4

42412 0 646351 28 .9 0 .67 .5 0 .4

4821 03 438147 18 .5 0 .38 .4 0 .2

4439 8 436145 I7 .6 0 .47 .8 0 .3

S S EM . L BM , lean body m ass calculated by us ing bioelectrical im pedance analy sis; V L ED , v e ry - low -en erg y d iet . T he re w ere no sig nif ican t m aine f f ec ts by A NO V A . See T ab le I f o r a fu ll d esc rip t ion of the V L ED s. S O P, 50 g prote in /d; bC , 1 0 g carbohy d rate/d ; 7 6C , 7 6 g carbohy d rate/d; 8 6C ,8 6 g c ar bo hy d rat e/ d.


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T ABL E 3Plasma substrate and ho rm one concentrations

S tat istical effe ctsG roup D ay 0 D ay 14 D ay 28 Carbohy drate Pro te in T im e Carb X tim e Pro X t ime

< 0 .001 0 .99 4 < 0 .001 < 0 .00 1 0 .5 7443 4 20 2275 1123 9 0 7 132 9 60

26 20 40073 5 10 4

2 7 4 1 3 6 166 6 56

284 9 44 665 3 84

3 0 5 5 4 0 464 1 45

2 1 7 1 61 9 7 2 01 8 9 2 02 4 0 SO

2 5 1 1 12 6 3 1 73 1 4 2 42 3 6 2 3

2 8 7 2 12 7 3 3 33 3 1 2 . 82 4 7 1 6

5. 6 0.35. 4 0.35 .8 0 .35 .4 0 .2

4 .2 0 .24 .8 0 .24 .0 0 .24 .6 0 .2

4 .1 0 .14 .6 0 .13 .6 0 .34 .8 0 .2

324 353 4 6 1 92 4 2 1 63 0 4 25

514 SO3 8 2 2 34 2 2 4 6321 29

454 473 2 2 2 73 6 6 4 02 78 23

4. 4 0.64 .5 0 .43 .9 0 .43.9 0.3

3 .6 0 .22 .9 0 .34 .6 0 .24 .8 0 .3

3 .2 0 .22 .7 0 .34 .3 0 .24 .6 0 .4

6677167127 64

7 868047337 84

7 977 857977 14

8 2 2089 1366 898 181. 1 0 .11 .7 0 .21. 0 0.11. 4 0. 1

0 .29 1 0 .57 5 < 0 .0 01 0 .18 6 0 .92 3

0 .00 3 0 .18 4 < 0 .00 1 0 .04 4 0 .89 7

0 .05 3 0 .03 3 < 0 .001 < 0 .00 1 0 .85 9

0 .71 3 0 .00 3 0 .002 0 .272 < 0 .001

0 .3 95 0 .52 7 0 .1 03 6 0 .5 59 0 .08 2

0 .061 0 .879 < 0 .0 01 0 .0 26 0 .464

0 .003 0 .016 < 0 .00 1 0 .0 70 0 .1 94

0 .009 0 .940 < 0 .00 1 0 .3 52 0 .3 53

15 2 2618 9 5114 9 19170 262 .0 0 .82. 2 0.21. 6 0.11. 8 0. 1

89 410 8 991 7

11 2 S

59 1211 1 2662 912 1 191.2 0. 11 .7 0 .21 .3 0 .61. 4 0 .192 3

11 0 896 8

10 6 6

8 4 510 7 78 4 89 96

I Se e Tab le 1 for a full descrip tion of the v ery -low -energy d iets . T here w ere no significant carbohy drate X pro te in or carb ohy d rate X protein X t imeinte ract ions. SO P, SO g pro te in/d ; 1OC , 10 g carb ohy drate /d ; 7 6C , 76 g carb ohy drate /d ; 86C , 86 g carbohy d rate /d .

2 SEM.

d ay 28 .Threonine w as the only am ino ac id that dem onstrated a

sig nif icant carbohy drate e ffec t and m e thionine w as the onlyone th at d em on st r at ed a sign i f i can t p r ot ei n ef f ect . T h r eon ine

96 V A ZQUEZ El A L

/3-Hy d rox y buty rate (mo l /L )SOP /1OCSOP/76C70P /1OC70P /86C

Free fatty ac ids (m g/L )SOP /1OCSOP/76C70P /1OC70P /86C

G luc os e (m m ol/L )SOP/lOC50P/76C70P /1OC70P /86C

U ric ac id ( mo l f L )50P /1OCSOP/76C70P /IOC70P /86C

B lood urea nitrogen (mm ol/L urea)SOP /1OCSOP/76C70P /1OC7OP/86C

C re at in in e ( t mo lIL )SOP/bCSOP/76C70P /bOC70P /86C

Ins ul in ( pm o l/ L)SOP /1OCSOP/76C70P /1OC70P /86C

T riio do thy ro nine (nm ol/L )SOP /1OCSOP/76C70P /1OC70P /86C

T hy ro xine (nm oiIL )SOP /1OCSOP/76C70P /1OC70P /86C

p lasm a pr otei n concen t r at i on w er e sim i l ar i n al l f ou r V L E D T he m ost p r om in en t t im e X d ie t inte rac tions w ere those o fgroups and w ere no t affec ted by the carb ohy drate or pro te in alanine and the b ranched-chain am ino ac ids .contents o f the V LED (T ab le 5) . F r om days 0 t o 14, t he concen t r at i on s of al an i ne, p h en y lal -

anine , and ty rosine w ere reduced , w hereas the concentrationsPlasm a am ino ac id s o f g lutam ine, m e thio nine , and threonine w ere no t affec ted . T he

B ecause p lasm a am ino acid s are sensitiv e ind ex es o f pro te in concentrations o f all the se am ino ac id s rem ained d ep re ssed atm e tabo lism , w e m easured their concentrations at day s 0 , 14 ,and 28 of treatm ent w ith each V LED . O v er tim e, the concen-tnations o f sev e ral am ino ac id s w ere s ignif icantly alte red (P 76C V L ED group, andm eth io n ine w as low er in the 70P than in the S O P V L ED gro up .

In con trast, the p lasm a con cen trations o f leuc ine and iso leu -c ine increased f rom day s 0 to 1 4 in all V L ED groups . V alinealso increased in all V L ED group s ex cep t in the 5 0P/76CVLED group . T he increases in the bran ched -cha in am ino ac id sw ere o f g reate r m agn itude in th e 1O C than in the > 76C V L EDgro ups , bu t th e d if f e rences be tw een the grou ps w ere sm all an dno t statis tically s ign if ican t. From d ay s 1 4 to 28 , th e concen tra-tio n s o f all th ree b ranched -ch ain am ino acid s d ecreased , bu tthey rem ained h igher than the day -0 con cen tration s in allg roups .

Ur ine n itrogenT h e largest rou te o f n itrog en lo ss in the body is the u rinary

trac t. T o de te rm ine w he ther th is rou te o f ex c re tio n w as d if f e r-en tially af f ected by the carbo hy drate o r p ro te in con ten ts o f th eV LED s , w e m easured to tal n itrog en daily d uring treatm en t.

T h e patte rn o f the u rinary ex cre tio n w as s im ilar w ith allV L ED s and show ed p rogressiv e , sign if ican t reduc tions w ithtim e (Figu re 1 ). T h e to ta l n itro gen excre tion w as s ig n ifican tlyaf f ec ted by the carbo hy drate con ten t. T he daily (Fig ure 1 ) andw eek ly av erag e (T ab le 6 ) u r ine n itrogen excre tio n w a s low erin the > 76C than in the 1OC g roups . T he carboh y drate ef f ec tw as app aren t th rough ou t the 28 d o f treatm en t (Figure 1 , T ab le6) .

T h e urine n itro gen ex cre tion w as also af f ec ted b y the V L EDpro te in con ten t. T he d aily (Figure 1 ) and the w eek ly dailyav erage ex cre tion s (T ab le s 6 an d 7 ) w ere h ig her in the 70Pgroups th an in the S O P group s. U rea and am m on ia accou n t f o rm os t o f th e n itro gen ex cre ted in the urine o f hum ans . T o asse ss

w he ther th e o bserv ed d if f e ren ces w ere due to ch an ges in u re -agenes is and /o r am m on iagenes is, w e also m easured the ex cre -tion o f the se m etabo lites .

T he daily av erage urea n itrog en ex cre tio n w as h ig hest du ringthe f irst w eek o f treatm en t and g radually decreased o v er tim ein all V L ED groups (T ab le 6 ). T he carbohy drate con ten t o f th eVLED s d id no t in fluen ce urea n itro gen excre tio n . H ow ever , itw as s ign if ican tly af f ec ted by the pro te in con ten t o f th e V L ED s(T ab le 7 ) .

In con trast w ith u rea n itrogen , there w ere no tim e-dependen tredu c tion s in the av erage daily u rin e am m on ia ex cre tion (T ab le 6 ).N one the les s, th e u rine am m on ia ex cre tio n show ed s ig n if ican tcarbo hy drate and pro te in e f f ec ts . D aily u rine am m on ia ex cre tionw as low er in the > 76C than in the 1O C grou ps, b u t h ig her in the70P than in the S OP V L ED group s (T ab les 6 and 7).S t o o l n itrogen

N ex t, w e de te rm ined w he ther the V L ED s af f ec ted th e lo sse so f n itrogen in the s too l. A s w ith u rine n itrog en , th ere w as aredu c tion in stoo l n itro gen ex cretion ov er tim e an d th ere w as ah igh ly sign if ican t carbohy drate e f f e c t. H ow ev er, th e carb ohy -d rate e f f e c t w as op pos ite to that o bse rv ed w ith u rinary n itro -gen ; ie, th e av erage d aily stoo l n itro gen w as h ig her in the> 76C than in th e 1OC V L ED group s (T ab le 6). T here w ere nod if f eren ces in s too l n itrogen b etw een the S O P an d the 7 0PVLED groups .

N itrogen ba lan ceN itrog en b alance also im prov ed ov er tim e in all V L ED

group s and w as n ear equ ilib rium by the f o u rth w eek o f treat-m en t in all g rou ps (Figu re 1 ). N itrog en balance w as s trong ly


6/11

S tati stic al e ff ec tsG roup D ay 0 Day 14 Day 28 C arbohy drate Prote in l im e Carb X tim e Pro X t ime

0 .212 0.8 98 < 0.0 01 0.244 0 .290

37 138 138 139 b

3 7 1 3 6 1391 3813 9 1 3 8 13 9 1 3 8 1

0.081 0.853 < 0.0 01 0 .091 0.2 38

0 .238 0.1 05 0.0 09 0 .773 0.898

0 .457 0.0 64 0.0 21 0.993 0.8 90

0 .076 0.5 21 < 0.0 01 0 .013 0.0 73

0 .727 0.1 23 0.1 84 0.176 0.5 33

0 .197 0 .447 < 0.001 0.020 0.4 74

0 .225 0 .123 < 0.001 0 .0 83 0 .719

0 .260 0 .039 0.5 52 0.7 79 0 .415

0 .329 0 .917 0.008 0 .08 4 0 .666

0 .030 0 .51 1 0 .348 0.0 72 0.244

0.2 36 0 .828 < 0.001 0 .278 0.517

0.1 64 0 .853 < 0.001 0 .014 < 0.001

I Se e T ab le 1 f o r a fu ll de scrip tion of th e v ery -low -energy diets. T h ere w ere no s ign if icant carbohy drate X p rotein or carbohy drate X p rotein X tim ein te raction s. S O P, S O g pro tein /d; 1OC , 10 g carbohy drate/d ; 76C , 76 g carbohy d rate/d ; 86C , 86 g carbohy d rate/d .

2 S EM .

9 8 V A Z Q UEZ E l A LTABLESPlasm a pro te in s and am ino acid s

R etin ol-b in din g p rote in (m gIL )SOP /bCSOP /7 6C70P/1OC7OP/86C

Prealbum in (m g/L )SOP /1OCSOP /7 6C7OP /1OC7OP/86C

A l b um i n ( g /L )SOP / b c5OP/76C7OP /1OC70P/86C

T otal p ro te in (g /L )SOP / 1OCSOP /7 6C7OP /1OC7OP/86C

A lan ine (p mo l /L )SOP /1OCSOP /7 6C7OP /1OC7OP/86C

G lutam ine (p mo l /L )SOP /bCSOP /7 6C70P/1OC7OP/86C

Iso leu cin e (p mo l / L )5OP/1OCSOP/76C7OP/1OC7OP/86C

Leu c in e (j.mo l / L )5OP / 1OCSOP /7 6C7OP /bOC7OP/86C

M e th io nin e ( tm o l/L )SOP / IOCSOP /7 6C7OP /1OC7OP/86C

Pheny lalan in e (mo l / L )SOP / 1OC50P/76C7OP /1OC7OP/86C

T hreonine (mo l /L )SOP /1OC5OP/76C7OP /1OC7OP/86CT y ros ine (mo l /L )SOP /1OCSOP /7 6C7OP /1OC7OP/86C

V aline (p mo l /L )SOP /bCSOP/76C7OP /1OC7OP/86C

4 3 5 2 3 1 4 3 0 4463 363 3624 82 3 13 2944 74 364 343

2 1 8 2 1 1 6 2 1 7 1 6 9 2 02 3 6 1 7 b 9O 1 4 1 9 8 1 02 4 1 2 2 1 5 3 1 5 1 4 2 1 52 3 4 1 8 1 9 6 1 4 1 9 1 1 9

6 1 2 6 0 1 5 8 1633 623 6 0 36 5 1 6 6 1 6 4 2682 672 632

3 4 0 4 2 2 0 4 2 0 1 8 2 1 6284 22 26 0 1 5 2 68 1 73 8 3 3 1 b 9 6 14 1 7 5 153 6 4 3 3 2 4 8 1 7 2 3 6 2 1

4 8 5 3 2 4 3 5 3 0 4 3 2 3 14 2 2 2 1 4 1 1 2 8 4 2 0 2 34 1 7 3 2 3 8 9 3 2 3 5 0 2 840037 39730 40230

585 9910 807655 7 86 735636 877 755534 746 776

1 5 1 1 1 2 0 0 1 8 1 7 2 1 014 7 1 0 166 15 160 1313 9 16 178 14 144 141 1 1 1 0 1 5 4 1 6 1 6 3 1 6

243 242 263272 243 2722 3 2 1 9 1 1 8 1223 243 233

543 484 433544 493 515504 512 4 4 3566 504 505

1 4 6 1 9 1 3 7 1 5 1 4 7 1 51 7 0 1 0 1 7 6 1 8 1 8 7 1 514 9 12 146 10 140 111 4 2 7 1 7 2 9 1 6 9 1 2

715 544 4 8 4674 583 544626 525 4 6 56711 6 0 4 596

2 29 22 2 78 3 0 236 232 2 4 1 9 2 1 6 1 5 2 0 5 1 520 0 21 283 20 230 201 7 7 1 4 2 3 0 2 1 2 5 1 2 2


7/11

-0- -

s o p / b clOP/bCsoisc7OP / 8 6C

.1 .0 4 8 1 I S 20 24 28

DAYS

PR OT EI N M ET A B O L I SM D U RI N G W EI G H T R ED U CT I O N 9 9

V0EE

1200

1000

80 0

800

40 0

80

20

-40

10 0V

1S0E

22028 0

.34g.

UR IN E N IT R OG E N

N IT R O G E N B A L A N C E

F IG UR E 1. U r inary ni trogen ex cretion (top) and ni trogen balance(bottom ) duri ng treatm ent w ith the f our very -l ow -energy diets (V LED 5) .i SEM . SO P, SO g protei n/d; 1O C, 10 g carbohy drate/d; 7O P,70 g protei n/d; 76C , 76 g carbohy drate/d; 86C , 86 g carbohydrate/d.

in f luenced by the carbohy drate content of the V L ED s. T heef f ect of carbohydrate w as highest duri ng the i ni t i al w eek oftreatm ent. T he dai l y (F i gure 1) and the w eek l y (T able 6)average ni trogen balances w ere l ess negati ve in the > 76C thanin the 1OC V L ED groups.

D uri ng the f i rst w eek of treatm ent, the ni trogen balance tendedto be less negati ve i n the 70P V L ED groups than in the SO P V L EDgroups (Figure 1 and T able 7). A s w i th the carbohydrate ef f ect, theef f ect of protein occurred m ainl y duri ng the i ni t i al w eek of treat-m ent. A f ter thi s peri od, the adv antage of the 70P groups di sap-peared and, as a resul t, the overal l protein ef f ect w as not statisti -cal l y si gni f i cant. N ote that the ni trogen balance in the 70P V L EDgroups i s som ew hat overestim ated because i t w as not correctedf or changes in B U N pool (T able 3).Co r r e l a t i o n s

T o assess horm onal f actors that could explai n the vari ati onsin ni trogen balance, w e correlated the ni trogen balance dataw i th pl asm a 13, 14, and insul i n concentrations. T he data w ereanaly zed consideri ng al l data points, and separatel y f or eachdiet group. W hen al l data points w ere considered together (n =124), there w as a signi f i cant correl ati on w i th 13 (r = -0.23),but not w i th 14 (r = -0.13) or i nsul i n (r = -0.17) concen-trations. H ow ever, w hen the data w ere anal yzed separatel y f oreach V L ED group, w e detected a highl y si gni f i cant (P < 0.01)

i nv erse correl ati on (r = -0.63, n 30) betw een ni trogenbalance and serum 13 in the 50P/1OC V L ED group, but not i nthe others (Fi gure 2). T he correl ati ons betw een ni trogen bal -ance and 14 and insul i n pl asm a concentrati ons w ere not si g-ni f i cant, regardless of how the data w ere anal yzed.

C h a n ges in lea n b od y m a ssT o a ssess ch a n ges in lea n b od y m a ss t h a t occu r r ed d u r in g t h e

study , w e calcul ated the cum ulati v e (day s 0 to 28) ni trogenlosses duri ng treatm ent w i th al l f our V L ED s (F igu r e 3). T h el argest l osses (3992 351 m m ol ) occurred i n the 50P/I O CVL E D gr ou p a n d t h e sm a l les t (1 723 344 m m ol ) occurred i nthe 70P/86C V L ED group. A ssum ing that 1 k g lean body m ass

,- contai ns 2355 m m ol (33 g) N (20), the average losses of leanbody m ass f or the 28 d of treatm ent can be calcul ated as I .69 0.14 and 0.91 0.14 f or the SO P/1OC and SO P/76C V L EDgroups, respecti vel y , and 1.37 0.23 and 0.73 0.24 f or the70P/1OC and 70P/86C V L ED groups, respecti vely . T he lossesi n l ean body m ass accounted f or 9.6-19.2% of the total w eightloss (T abl e 2) .

T he > 76C V L ED groups had signi f icantl y l ow er cum ula-ti ve ni trogen losses than the 1OC V L ED groups (1869 392and 361 1 328 m m ol , P = 0.003). T he cum ulativ e ni trogenlosses w ere also l ow er i n the 70P than in the SO P V L EDgroups, but the di f f erence betw een the tw o w as sm al l and notstati sti cal l y si gni f i cant (2326 430 and 3171 327 m m ol ,respectively, P 0.279).

DI SCUSSI ON

T hi s study show s that vari ous aspects of protei n m etabol i smduri ng w eight reducti on are i ndependently af f ected by thecarbohy drate and the protein contents of the V L ED s. O n theone hand, carbohydrate signi f i cantl y af f ects ur inary am m oniaand total n i trogen excreti on, stool n i trogen excreti on, ni trogenbalance (T able 6), and plasm a threonine concentrati ons (T able5). O n t h e o t h er h a n d , p r o t e in , sign ifica n t ly a n d in d ep en d en t lyf rom carbohydrate, af f ects uri nary am m onia, urea ni trogen,total ni trogen excretion (T able 6) , pl asm a B U N (T able 3), andm ethioni ne concentrati ons (T able 5). T he ef f ects of carbohy -drate and protei n on uri nary and stool ni trogen excreti on persi stthroughout the 28 d of the study but the net ef f ect i n ni trogenbalance w as greaten duri ng the i ni t i al 14 d of treatm ent. N ever-theless, of the tw o, the ef f ect of carbohy drate appears to pre-dom inate w hen both are present i n the higher am ounts andbecom es the f actor that determ ines the net dai l y and cum ulati veni trogen losses (Fi gures 1 and 3).

Carbohydrate ex erts i ts protei n-spari ng ef f ect v i a severalm echani sm s. O ne m echani sm is by reducing am m oniagenesi s(T able 6). H ow ever, th is ef f ect is sm al l and unl i kel y to accountf or the enti re acti on of carbohydrate. A nother m echanism is bym aintai ni ng higher pl asm a concentrations of horm ones such asinsul i n, 13, and 14. T hese horm ones are know n to i nf luenceprotei n turnover (21, 22) and w ere al l hi gher i n the plasm a ofthe > 76C than in the 1O C V L ED groups (T able 3). T heseresul ts agree w i th prev i ous studi es that show ed higher pl asm athy roi d horm one concentrati ons w i th hi gh-carbohydrateVL E D s (3 , 1 3 , 23-25) and w i th others that have identi f i ed 13as the m ost im portant regulator of protei n sparing duri ng en-engy depri vati on (26).


8/11

, - # { 1 4 9 } 03p < 001

, - 121p - 0 . 2 0

0E=CDE00CD

250200150100

50

250200150100

500

l o p ! 8 6 C

.%

. . . ;., . . 1 -_ . . 1 !

5 0 PI 7 6 C, -004. p - O i l

, - 0 . 1 2p - 0 . 5 1

0EE

0

.0z

aE

0

.. .%

P ro t e in in t ak e

100 V A Z QU EZ El A LTABLE 6N itrog en m etab ol ism

Sta ti sti cal ef fectsCarbo- Carb X Pro X

G roup W eek 1 W eek 2 W eek 3 W eek 4 hy drate Protein T im e t ime t imeU rine ni trogen excreti on (m m ol /d) < 0.001 < 0.001 < 0.0()l 0.848 < 0.O()l

SOP/ 1 OC 7 4 2 2 4 2 6 1 5 1 7 5 7 1 1 0 5 3 8 1 05 OP/ 7 6 C 6 0 9 1 7 5 1 7 1 7 4 8 3 1 4 4 7 1 1 770P/bOC 857 30 846 21 819 19 783 157 0 P / 8 6 C 7 8 8 2 8 7 6 6 1 8 7 3 4 2 0 6 8 8 2 2

U rine urea ni trogen excretion (m m ol /d) 0.320 < 0.001 < 0.001 0.830 0.003SOP/ b C 5 6 5 3 4 4 9 8 3 3 4 5 1 3 7 4 4 1 2 250P/76C 481 30 426 3 5 392 3 5 397 277O P/l OC 601 42 648 35 588 43 576 227O P/86C 644 4 9 662 36 546 46 531 4 7

U rine am m onia excretion (mm ol /d) 0.013 < 0.001 0.096 0.208 < 0.00150P/lO C 25 4 24 3 21 3 27 55O P/76C 17 2 14 2 12 2 13 27OP/I O C 36 3 4l 3 39 3 39 470P/86C 35 3 37 2 34 3 32 3

Stool ni trogen (m m ol /d) 0.003 0.843 < 0.(X )1 0.108 0.113SO P/bOC 60 4 50 3 40 2 40 25OP/76C 100 5 80 4 70 4 70 47O P/1OC SO 3 40 I 40 4 SO 170P/86C 70 6 80 6 90 4 60 4

N itrogen balance (m mol /d) 0.0()3 0.331 < 0.001 0.820 < 0.0015OP / bOC - 2 6 8 2 7 - 1 2 8 1 7 - 8 3 1 1 - 5 2 1 15OP/76C - 169 19 - 61 16 - 29 14 - 15 167OP/1OC - 153 29 - 125 21 - 97 19 - 63 157OP/86C -112 29 -8119 -44 21 +823

S ee T able I f or a f ul l description of the very- low -energy di ets. SO P, SO g protei n/d; bC, 10 g carbohydrate/d; 76C , 76 g carbohy drate/d; 86C , 86 gcarbohydrate/d.

2 S E M .

O ur resul ts also prov i de new insi ght into the prev i ousl yrecogni zed correl ati on betw een ni trogen balance and serum 13concentrati ons. Y ang and V an I tal l i e (12), F i sl en et al (27), andK aptei n et al (28) prev i ously reported a si gni f icant inverse

5 OP I 1 OC 7 OP I 1 OC

a n .E 1S 0 10 0 2t5 4 .o i i us

N it ro ae n B a la nc e (m m o ll dav )F IG U R E 2. Relation of plasma tri i odothyronine (13) concentration to

ni trogen balance for the four v ery -low -energy diets (V L ED s) . SOP, SO gprotein/d; bC , 10 g carbohydrate/d; 7OP, 70 g protein/d; 76C , 76 gcarbohydrate/d; 86C , 86 g carbohy drate/d.

correl ati on betw een ni trogen balance and serum 13 (or changesin 13) duri ng treatm ent w i th V L ED s. W e conf i rm ed theseresul ts, but onl y i n the SO P/1OC V L ED group (Figure 2).Col l ecti vel y , these resul ts suggest that the correl ati ons betw eenthese f actors are com plex and are af f ected by the com posi ti onof the V L ED s. For ex am ple, Fi sl er et al (27) and K aptei n et al(28) studi ed pati ents consum ing V L ED s that prov i ded proteins

5000

4500

4000

35003000

2500

2000

1500

1000

500

F IG U R E 3. Cum ulati v e (days 0-28) losses of ni trogen dur ing treatm entw i th the four very - low -energy diets (V LED s). SEM . H igh carbohy -drate, V L ED s w i th > 76 g carbohydrate/d; low carbohy drate, 10 g carbo-hydrate/d.


9/11

PR OT E IN M ET A B O L IS M DU R IN G W E IG H T R EDU CT IO N 101TABLE 7S tatistic ally s ign if icant in teractio ns, by w eek

W eek 1 W eek 2 W eek 3 W eek 4U rin e n itro gen ex cre tio n (m mo l/d)

S O P 68 3 23 5 72 iD 53 2 1 3C 5 11 12 d70P 816 2 b 2 79 9 l6 2 76 8 iD 2 72 6 17c2

U rin e urea n itro gen (m mol/d)S OP 526 26 4 73 20 442 2 4 4 27 1D70P 638 28 6 64 2 12 57 0 2 7 5 51 32h2

U rine am monia nitro gen (m mo l/d )S O P 212a b82a 163a 203a7O P 36 2a2 40 22 3 7 2a2 3 7 2a2

S t o o l nitrogen (m m ol/d)S OP 797a 66D 596 5777 0 P 6 2 8 a S 7 b f f 6 4 I P s 5 6 a

N itrog en balance (m mol/d)SOP - 2 2 4 2 1 - 1 0 1 1 4 70 P - 129 21 2 99 14 - 66 16 20 16d I S EM . M eans in a row w ith d if f erent le tte r sup erscrip ts are sign if icantly d if f e rent , P < 0.005. Se e T ab le 1 f o r a f u ll d e sc rip tion o f the

v e ry -low -en erg y die ts. S O P, S O g p ro tein /d; 7O P, 70 g prote in /d .2 S ign if icantly d if f e rent f rom S OP, P < 0.005.

on ly . A lthou gh Y ang and V an Itallie s tud ied th ree patien tsconsum ing p ro te in o n ly and th ree p atien ts consum ing 50% ofenergy as p ro tein s an d 5 0% as carbohy drate s, th e to tal carbo -h y drate co nsum ed w as le s s than th e am oun t p rov id ed in th e> 76C V L ED used in th is study .

A n add ition al m ech an ism by w h ich carbohy drate m ay sparepro te in is by redu cing th e rate o f g lucon eo genesis . A f ter 3 d o fa com p le te f as t, g ly co gen s to nes are dep le ted and g lu co se isp redom in ate ly p rod uced de no v o (29 ). S im ilar ev en ts are p re -d ic ted to occur during treatm en t w ith V L ED s ex cep t th at theg ly cogen s to re s and th e rate s o f g luconeog en es is m ay v aryw id e ly depend ing on the carb ohy drate con ten t o f th e V L ED .T he m os t im portan t g lu coneogen ic p recurso rs are lactate , g ly c -e ro l, and am ino ac id s (30 ). D uring a short f as t, ob ese patien tsconv erted an av erage 55 .9% (range 3 0 .4 -81 .3% ) o f the g ly c -eno l p rod uced by lipo ly s is in to g lucose an d th is accoun ted f o r8.3% o f the to tal g lucose h ep atic ou tpu t (31 ). R ecen tly , w esh ow ed that af te r an ov ern igh t f as t in ob ese w om en , 46-49% ofthe g ly ce ro l p rodu ced f rom lipo ly s is w as conv erted in to g lu -co se and that accou n ted f o r 10 -11% o f the to tal g lucose hepaticou tp u t (32 ). D uring w e igh t reduc tion w ith V L ED s , the con tn i-bu tion o f g ly ce ro l to g lu co neogenes is in c reased . H ow ev er, th einc rease in g ly ce ro l rate o f appearance and in the rate o fconv ersion in to g lucose w as m odes t and , at its peak , accou n tedf o r no m ore than 16% of the endog en ous g lucose p roduc tion(31 , 32 ).

T o o ur k now led ge , th e re has been no s tudy o f the rate o fg lucon eo genesis f rom lactate during w e ig h t redu ction . H ow -ev en , b ecause d ie tary g luco se is th e m ajo r (b u t no t th e on ly )source o f lac tate in the body , it is reasonab le to assum e thatg lucon eo genesis f rom th is p recurso r w ill b e low d uring treat-m en t w ith V L ED s , e spec ially w h en the carbo hy drate con ten t islow . T h is im p lie s that am ino ac id s are th e m os t im po rtan tg lu co neogen ic p recurso rs during w eig h t reduc tion w ithV L ED s . In th is study , patien ts in th e h igh -carbo hy drate V L EDgroups co nsum ed 66 -76 g m ore canb ohy d rate /d than d id thepatien ts in the low -carboh y drate V L ED groups . E v ery th in ge lse be ing equal, th is w o u ld in d icate that g lu coneogenes is f romam ino acid s w ill b e h igh er in the low -carbo hy drate V L ED

g roups . T h is, in part, e x p lain s the h igher u rea, am m on ia, andto tal n itrogen ex cretion s in th e 1OC V L ED group s com p aredw ith the > 76C grou ps. W e canno t, h ow ev er, de term in ew he ther am ino ac id s f rom end ogenou s sources (ie , p ro te inb reak dow n) and f rom d ie tary p ro tein s are u sed to the sam ed eg ree f or g lu co neogenes is .

T he re su lts o f th is s tudy also show that V L ED s th at p ro v ide70 g pn o te in /d are no t superio r to tho se pro v id ing S O g pro tein /df o r p ro te in sparing during w e igh t reduc tion reg ard les s o fw he ther they con tain h igh or low am oun ts o f carboh y drate .T h is conc lu s io n is sup ported b y the f o llow ing lin es o f ev i-d en ce : Firs t, af te r the in itial w eek o f treatm en t, th ere w as nod if f eren ce in daily (Fig ure 1 ) o r w eek ly (T ab le s 6 and 7 )n itro gen balances b e tw een the 7O P and the S OP V L ED grou ps.T he m ain m echan ism that accoun ts f o r the lack o f d if f e rence isthat un eagen es is and am m on iagenesis w ere h igher in the 7OPV L ED gro ups . T h e orig in o f the ex cess am m on ia an d urean itro gen can no t be ascertained f rom the re su lts o f th is study ,b u t the m os t lik e ly sou rce is d ietary p ro tein . S econd , thecum u lativ e lo sses o f n itrogen f o r the 28 d o f treatm en t ares im ilar in th e 70P and the S O P grou ps (Figure 3 ). T h is issu rp ris ing co nsidering that w e are lik e ly to h av e ov ere s tim atedn itro gen balance in the 70P groups becau se w e d id n o t co rrec tth e re su lts f o r the changes in the B U N poo l (T ab le 3 ) an dbecau se o f the inh eren t b iase s o f th e n itrogen b alance at h igherp ro te in in tak es (33 ). L astly , all o the r index es o f p ro te in nu tri-tion m easured such as the p lasm a co ncen tration s o f alb um in ,p realbum in , and am ino ac id s (w ith the ex cep tion o f m e th io -n ine ) w ere sim ilarly af f ec ted in the S O P and 70P V L ED grou ps.N o ne th ele s s, d esp ite the se f ind in g s, it is p ruden t to recom m endth at V L ED s pro v ide 70 g p ro te in /d because th is am oun tw ou ld prov ide a greater m arg in o f saf e ty f o r m os t peop le .

O ur re su lts also ind icate that th e u se o f > 7 6 g canbo hy -d rate /d in stead o f 1 0 g carbo hy drate /d in an isoenenge tic V L EDw ill resu lt in th e sparing o f an ad d ition al 0 .54 -0 .6 4 k g o f leanbod y m ass in 2 8 d , depend ing o n the p ro te in con ten t o f th eV L ED . W e do no t k now w he ther the ef f ect o f carbo hy drate onpro te in sparing w ou ld pers ist o r d isappear if p atien ts w eretreated f o r lon ger period s o f tim e . B y 28 d , patien ts in all


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10 2 V A ZQUEZ E l A L

g roups w ere in n ear n itrogen balance (Figure 1 ), and it isreaso nab le to assum e that af ter that tim e th e d if f e rences b e-tw een the group s w ou ld no t co n tin ue to inc rease . If that is th ecase , th en it can be argued th at th e re lativ e adv an tage o fh igh -carbo hy drate o v er low -carbohy d rate V L ED s is lik e ly n o tto b e o f clin ical sign if icance . T h is is supported b y th e absenceo f adv erse reaction s in any o f th e g roup s and by the re lativ e lysm all lo s se s o f lean body m ass in all V L ED s , w h ich in th ew ors t g ro up w ere les s th an pred ic ted (19 .2% o f w e igh t lo ss )(Fig ure 3 ). T h ese re su lts also ag ree w ith recen t stud ie s o f bod ycom pos ition af te r w e igh t reduc tion w ith V L ED s (34 ). T here -f o re , it can be conc luded that all th e V L ED s used in th is s tudyto a certain ex ten t p rev en ted ex cess iv e lo s se s o f lean bod y m assduring w eigh t redu ction . H ow ev er, in the in te rp re tation o f ourresu lts tw o f acto rs sho u ld be con sidered . Firs t, ou r su b jec tsw ere all w om en , re lativ e ly h ealthy and sev ere ly o bese . T here issom e ev idence to ind icate th at n itrogen con serv ation m ay bed if f e ren t in m en and w om en an d in m oderate and sev ereo besity (35 , 3 6 ). T here f o re , cau tion shou ld b e ex erc ised inex trap o lating these re su lts to o ther p opu lation s . S eco nd , w eo n ly s tu d ied tw o in tak es o f p ro te in an d tw o in tak es o f canb o -h y drate and canno t conc lude th at the se are the op tim al am ou n tsneeded f o r p ro te in sparing . M ore s tud ie s are need ed to inv es -tigate w h ether h igher am ou n ts o f carb ohy d rate an d /o r p ro te inw ill hav e greater p ro te in -sparing e f f ec ts.

A no ther in te re sting f ind ing o f th is stud y is th e dem o nstrationo f h igh er s to o l n itrogen lo s se s in th e h igh -carbo hy drate V L EDg roups , w h ich w as independen t o f th e p ro te in con ten t (T ab le6 ) . T he reasons f o r the h igh er s too l n itrogen in the h igh -carbo hy drate V L ED gro ups are uncertain . D iarrhea d id no toccur in any gro up an d th is f in d ing cann o t be ex p lained byd if f eren ces in s too l w e igh t. M os t o f th e n itrogen in stoo l isas soc iated w ith bacte ria (37 ), an d it is po ssib le that bac te rialp ro lif eration w as h igher in the > 76C V L ED grou ps. T h isex p lanation is suppo rted by prev iou s s tud ie s in h ealthy ad u ltsthat show ed h igh er s too l n itrogen w ith h ig h -carboh y drate d ie ts(38 ) .

R etino l-b in d ing pro te in and prealb um in are pro te in s w ithsh ort half -liv e s an d the ir con cen tration s in p lasm a are f re -quen tly u sed as ind ex es o f p ro te in nu trition (39 ). W e de tec tedno d if f eren ce in th e p lasm a con cen tration s o f th is p ro te in sbe tw een the 50 - and 7 0 -g pro te in V L ED s. O n e possib le ex p la-nation o f th is f ind ing is that a pro te in in tak e > 70 g /d isrequ ired to m ain tain no rm al p lasm a concen tration s o f the sep ro te in s . O ther in v estigato rs hav e show n that th e se p lasm apro te in s are add itionally and in dependen tly af f ec ted b y th eenergy and carboh y drate con ten ts o f th e d ie t (39 , 40 ). W e w ereunab le to de tec t an e f f ec t o f carbo hy drate on p lasm a pro te in s(T ab le 5 ), and sim ilar re su lts w ere ob tained by H o f f en e t al(41 ) . T h is seem s to ind icate th at u nder the co nd itio n s o f ourstud y , ne tino l-b ind ing p ro te in and prealbum in are m o re sen s i-tiv e to energy than to pro te in depriv atio n .

In add itio n to the ir e f f e c ts on pro te in m e tab o lism , theV L ED s used in th is stud y prod uced o ther m etabo lic e f f e cts thatdese rv e m en tion . T he 1O C V L ED group s had s ig n if ican tlyh ig her p lasm a uric ac id and sign if ican tly low er p lasm a g lucoseconcen tration s than the > 76C V L ED gro ups . A lthough b o tho f the se index es rem ained w ith in the norm al range (T ab le 3 ),th e se f ind ing s sugg est that gou t and hy p og ly cem ia m ay o ccu rm o re f requen tly in su scep tib le patien ts if th ey are treated w ith

V L ED s that con tain low (< 10 g /d ) rath er than h igh (> 76 g /d )am oun ts o f carbo hy drate .

In sum m ary , by s tudy ing V L ED s that p rov ide tw o am oun tso f p ro te in and tw o am oun ts o f carbohy drate , w e w ere ab le tod ete rm ine the ind ep en den t e f f e c ts o f p ro te in an d carb ohy drateon sev eral index es o f p ro te in n u trition d uring w e igh t redu c tion .O ur re su lts show ed that the to tal carbohy drate and p ro te inin tak es w ere b o th im portan t f o r p ro te in sparing d uring w e igh treduc tion . Furtherm o re , ou r re su lts show ed th at the se e f f ectsw ere add itiv e and the bes t p ro te in sparing w as o b tain ed w iththe V L ED that p ro v ided 70 g pro te in and 86 g carbo hy drate /d .Fu rther stud ie s are need ed to d ete rm ine w he ther g reate r p ro te insp arin g can be ach iev ed w ith V L ED s that con tain h igheram oun ts o f p ro te in and carbohy drate. A

W e are ind eb ted to ludy A rch and the nurse s o f th e C lin ical R esearchC en te r o f the U n iv e rs ity o f Pittsbu rg h M ed ical C en te r f o r the ir he lp du ringthe p erf orm ance of th ese stu dies and to Janine Janosk y and K im L a fo rs ta ti st ic al as si st an ce .

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vasquez 1995 paper

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