frutose e metabolismo

8/8/2019 Frutose e Metabolismo

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2652 0892-6638/90 /0004-2652/$01 .50 . FASEB

M etabolic effects of d ietary fructoseJU DITH HA LLFRISCHGeronto logy Resea rch Center, N atio na l Institute on Aging Baltimore, M aryland 21224, USA

ABSTRACTFructose, a naturally occurring hexose, is a c ompon en tof many fru its, vegetables, and sw eeteners. B ecause ofthe introduction of high fructose corn sweeteners in1967, the am ount of free fructose in the diet of Ameri-cans has increased substantially in the last 20 years.F ructose is sw eeter, more soluble, an d l es s g lu co ge ni cthan glucose or sucrose, so it has been recomm endedas a replacement for these sugars in the diets of d ia-betic and obese people. Although an acute dose of fruc-tose causes smaller increases in glucose and insulinthan a comparable dose of glucose, there are a numberof changes after dietary adaptation that m ay reduce itsdesirability as a sugar replacement in certain segm entsof the population. F ructose is absorbed prim arily in thejejunum and metabolized in the liver. When consumedin excess of dietary glucose, it m ay be malabsorbed.Fructose is more lipogenic than glucose or starches,and usually causes greater elevations in trig lyceridesa nd s om e tim es in c holesterol tha n o th er carb ohy drate s.D ietary fructose has resulted in increases in blood pres-sure, uric acid , and lactic acid. People who are hyper-tensive, hyperinsulinemic, hypertrig lyceridemic, non-insulin-dependent diabetic, or postmenopausal aremore susceptible to these adverse effects of dietaryfructose than healthy young subjects. A lthough con-sumption of fructose as a component of fruits andvegetables is an unavoidable consequence of eating ahealthy diet, added fructose seem s to provide little ad-vantage over other caloric sweeteners and comparesunfavorably to complex carbohydrates in susceptiblesegments of the population . HALLFRISCH, J. Meta-bolic effects of dietary fructose. FASEB j 4: 2652-2660; 1990.Key Words: fructose glucose t ol er an ce h yp er in su li ne mi adiabetes triglycerides . uric acid

FRUC1DSE, ALSO CALLED LEVULOSE AND fruit sugar, is anaturally occurring keto sugar. It is found in fruits andvegetables, and makes up approximately 50% of honeyand sucrose. F ructopyranose is the only known crystal-line form of fructose and it is probably the sweetestnaturally occurring sugar. A lthough intakes of thenatural sources of fructose have been reasonably stable

for the last 20 years, the in troduction of high fructosecorn syrups in 1967 has led to an exponential increasein free fructose in the food supply of the United S tates(1). F ructose may have some metabolic advantages forcertain segments of the population. In 1874, fructosewas reported to be better tolerated than sucrose or glu-cose by diabetic persons (2). However, other metaboliceffects may be detrim ental to the health of other seg-ments of the population (e.g ., hypertrig lyceridem ics).In view of the recent increase in consumption of freefructose in the United S tates, th is review w ill discusssources of fructose in the diet, present and projectedconsumption levels, d igestion and absorption, metabo-lism , recent reports of metabolic effects in humans,where possible, or anim als, and make recommenda-tions for specific segments of the population.

CONTENT OF FRUCTOSE IN FOODSFructose (a-D -fructofuranose) is the predom inant mono-saccharide (3) in a number of fru its including apples,grapes, oranges, and watermelon (Table 1). Vegetablesmay contain by weight 1 to 2% free fructose and up to3% fructose as sucrose. These low percentages by weightmay constitu te a significant percentage of the totalcalories. For example, watermelon is 90% water byweight, 0 .6% protein, and 0.4% fat. Fructose accountsfor about 60% of the calories (40% from fructose aloneand 20% as fructose from sucrose). Inulin , a polymerof fructose (f3-D -fructofuranose linked by 2, 1 bonds)not absorbed by the human intestine, is present inchicory, sweet potatoes, and Jerusalem artichokes. F ruc-tose also occurs in some legumes as the trisaccharideraflinose (a-D-galactopyranosyl-(l ,6)-a-D-glucopyranosyl-( l ,2- l1-fructofuranoside) an d th e te tra sac ch arid e sta ch yo se(a-D-galactopyranosyl-(l,6)-c-D-ga1actopyranosyl-(1,6)-a-D-glucopyranosyl-( l,2)-f3-D-fructofuranoside) . These com -pounds are not absorbed by the human small in testine.They are, however, fermented by bacteria in the largein testine, and may be sources of the flatu lence thatoccurs after digestion of legumes. Fructose is found ina variety of sweets either free or as a component of su-crose, a disaccharide containing 1 molecule of fructoseand 1 molecule of glucose. Honey provides the h ighestconcentration of fructose (42.4% of weight) as a natural

A ddress reprint requests to: Judith H allfrisch , M eta bo lism S ec-tion, Gerontology Research Center, 4940 Eastern Ave., Baltim ore,M D 21224, USA .


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M ETABO LIC EFFE CTS O F D IE TA RY FR UC TO SE 2653

TABLE 1. S el ec te d s ug ar c on te nt o f foods

Food G lucose F ructose Sucrose Total sugars

FruitsA pple, raw 2.3 7.6 3 .3 13.3B anana, raw 4.2 2 .7 6 .5 15.6Cherry, raw 8.1 6 .2 0 .2 14.6G rape, raw 6.5 7.6 0 .4 18.1P ineapple, raw 2.9 2 .1 3.1 11.9Watermelon 1.6 3 .3 3.6 9. 0

Vegetab lesCarro t, raw 1.0 1 .0 3.6 6 .6Corn, sw eet 0 .5 0 .3 1 .5 2 .6Onion, raw 2.4 0 .9 1.3 6 .2Peas, cooked 0 .2 0 .1 4.8 5 .8Tomato , raw 1.1 1.4 0 2 .8

LegumesB eans, w /pork 1 .6 1.4 4.3 8 .3Chick-peas 0 .1 0 .1 1.2 4 .8Lentils, cooked 0 0 .1 0.5 1 .8Peanuts, dried 0 .2 0 3.8 4 .3Soybeans 0 .1 0 .2 0.5 3 .0

SweetsCorn syrup 14.9 1 .2 2 .2 37.0Honey 33.8 42.4 1.5 81.9M olasses 7.4 7.9 26 .9 42.8Maple syrup 2.3 0.9 59.1 62.3Brown sugar 5 .2 0.4 84.3 89.9

Processed foodsFru it cocktail 6.0 6.0 3 .3 15.3O range ju ice 5.3 4.6 0 .7 10.6Bread , white 1 .8 1.5 0 .1 3.9Fruitcake 11.3 11.3 20.5 43.1Cola 4.0 4.4 2 .1 10.6M ilk chocolate 0.2 0.1 46.8 52.1Toffee 6.7 5 .2 40.9 55.4Raisin bran 7 .3 8.2 10 .1 26.6Shredded wheat 0.1 0 0 .3 0.4Cherry brandy 16.5 16.1 0 32.6

Grams per 100 g e dib le p ortio n. Adapted from ref 3.

sw eetener; corn sugar is mostly glucose; cane andmaple sugar are predom inantly sucrose; molasses con-tains mostly sucrose, but is 8% fructose.

Fructose is more soluble in water than sucrose or glu-cose. It is the difference in this property, solubility , thatmakes fructose corn sweeteners the more popularsweetener for beverages and canned fruits, whereassucrose is more popular for baked goods. S ince fructosetends to form crystals less readily than sucrose, it ispreferred in some candies in which crystallization is notdesired. Canned fruits and juices contain 4-8% fruc-tose. Baked products may contain 1-2% fructose unlessthey are predom inantly fruit, such as fruit pies orcakes, which may contain as much as 11% fructose. A sa result of the lower cost of corn compared to canesugar, carbonated beverages produced in the UnitedS tates now almost exclusively use high fructose cornsweeteners rather than sucrose. H igh fructose cornsweeteners, in troduced in 1967, are produced fromisom erization of glucose syrups extracted from corn asstarches and dextrins and then hydrolyzed . F ructose ac-counts for 4-6% of the weight and 50% of the calories

of carbonated beverages. M ost candies contain smallam ounts of fructose. If they are m ade w ith honey theymay contain 7-8% fructose. The fructose content ofbreakfast cereals ranges from nil to about 10% of dryweight.

PRESENT CONSUMPTION LEVELS OFFRUCTOSE IN THE UNITED STATESFructose consumption as a com ponent of corn sw eeteners(1) has increased 10-fold since 1975 (Table 2). Per capitaconsumption of th is source alone accounts for 49.1pounds/year. These data are reported by the U.S.Departm ent of A griculture as per capita consumption ,but are based on the disappearance of foods in the foodsupply and do not adjust for waste. A lthough refinedsucrose in take (cane and beet) has declined from 89.2to only 62.1 pounds/year in the last 15 years, overallcaloric sw eetener consum ption including refined sugars,honey, syrups, and corn sweeteners has increased from118 pounds for 1975 to 134.2 pounds estim ated for1989-an increase of 14% . Caloric sweeteners accountfor a mean of more than 165 g/day for every man,woman, and child in the United S tates. F ructose fromcorn sweeteners and honey accounts for approxim ately32 g/day. Fructose as a com ponent of refined sugar addsapproximately 39 more g/day . These figures do not in-clude any fructose that is consum ed as a component offru its and vegetables or other sources. Fru its andvegetables account for 10-15% of total simple sugars,but data on the proportion of fructose are not available .The rate of replacement of cane sugar w ith fructosecorn sweeteners seems to be reaching a plateau as isoverall sugar intake; however, m etabolic effects on thepopulation from this rapid change from the 1970s to the1980s may not be apparent for some tim e. F ructose (4kcal/g) from caloric sweeteners now accounts for ap-proximately 284 kcal/day, or about 8% of total calorieintake based on per capita kilocalorie availab ility of3400/day (4).

TABLE 2. U.S. per c ap it a c on sum pt io n o f c al or ic s we et en er s

Year Refinedsucrose HFCSb Honey T ota l s we ete ne rs

lbs dry wt/year1975198019851989

89.283.663.462.1

4.9 1 .018.0 0 .844.1 1 .049.1 1 .0

118.0123.9132.8134.8

g/day1975198019851989

11 110 47977

6 122 155 161 1

14 715 416 516 8

Ad apted from ref 1. bHFCS High fructos e c orn sw ee te ne rs.


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2654 Vol. 4 June 1990 T he F AS EB J ou rn al H A L L FR I SC H

DIGESTION AND INTESTINAL ABSORPTIONO F FR UC TO SEStudies exam ining digestion and absorption of fructosehave been reviewed by Reiser (5). In humans, sucroseis the only usable dietary source of fructose that re-quires hydrolysis before it is absorbed by the small in-testine. A lthough fructose absorption was thought tooccur largely by facilita ted diffusion, more recent evi-dence indicates that, in the rat in testine , fructose trans-port may be partially active and carrier-m ediated. Therate of fructose absorption is in termediate between therates of actively transported sugars such as glucose andgalactose and the rates of passively transported sugars.Fructose transport models based on studies of isolatedintestinal rat cells or in testinal segments indicate that itis probably Na-independent and mediated by a carrierin the brush border that is d istinct from that for glucosetransport. S ince fructose transport can occur against aconcentration gradient, it is an active mechanism thatrequires energy. This is confirm ed by reported inhibi-tion of transport by dinitrophenol and fluoride. Trans-port of both glucose and fructose is greater in the jeju-num than in the ileum . Fructose absorption appears tobe enhanced by the presence of glucose. When carbo-hydrates such as lactose or fructose are not absorbed bythe human small intestine, h igh osmolarity of the gutcontents causes secretion of flu ids into the gut, whichcauses abdom inal distention, cramps, and increasedgastrointestinal motility. The undigested carbohydrateis then fermented in the colon, producing CO2 andhydrogen. Increased breath hydrogen can be measuredand is a marker for the degree of malabsorption of orintolerance to various carbohydrates. In humans, fruc-tose given alone or in excess of glucose resulted ingreater breath hydrogen than an equal amount of glu-cose alone, fructose w ith an equal amount of glucose,or sucrose, indicating that fructose was not absorbed ascompletely as glucose or sucrose (6). Sorbito l m ay ag-gravate th is malabsorption (7). Consumption of exces-sive amounts of fru its and/or juices contain ing fructosehas been proposed as a cause of chronic diarrhea insome children (8). In humans, a small amount of fruc-tose is converted into glucose or lacta te w ithin the epi-thelial cell.

A fter transport into the epithelial cell, fructosediffuses to the serosal side. The majority of the fructoseenters the portal blood and is transported to the liverfor metabolism . Increasing the amount of fructose inthe diets of baboons and rats causes an increase in therate of in testinal fructose transport (5). To understandthe mechanism of improvement in athletic performancereported with carbohydrate-loading, a number of studiesinvolving exercise have exam ined differentia l gastricemptying and absorption rates of various carbohydrates.There is controversy as to whether gastric emptyingrate is dependent on the osmolality of stomach contentsor whether gastric emptying is controlled by a feedbackmechanism dependent on the number of calories deliv-ered to the duodenum . In a study of endurance-trainedathletes, gastric emptying rates of 400 ml of various

concentrations of glucose, fructose, and glucose-polymersolutions were determ ined by aspiration from nasogas-tric tubes. A t rest, gastric emptying rates were faster forisocaloric fructose and glucose-polymer solutions thanfor isocaloric glucose solutions (9). F ructose and glucose-polymer solutions presented more calories to the smallintestine for absorption more rapidly than did com -parable concentrations of glucose. Depletion of muscleglycogen and the subsequent fall in blood glucose thatoccur during prolonged exercise result in fatigue. B loodglucose levels of athletes were recorded both at rest andduring prolonged moderate exercise when the athletesdrank glucose, fructose, or glucose-polymer solutions(10). During exercise, blood glucose remained stablew ith both fructose and glucose ingestion . However, glu-cose utilization from the fructose solution was lowerthan from glucose. Therefore, even w ith the faster gas-tric emptying rate , although blood glucose was main-tained, fructose may not be an advantage in terms ofenergy availability.METABOLISM OF FRUCTOSEIn humans and the rat, fructose is metabolized prim arilyin the liver, although both the small in testinal mucosaand kidney also contain the enzymes necessary for thecatabolism of fructose (11). There is m inimal utilizationof fructose in peripheral tissues. The initial step in thecatabolism of fructose and other sugars is phosphoryla-tion . F ructose can be phosphorylated either by hexo-kinase, which occurs throughout the body and phos-phorylates a number of 6 carbon sugars at carbon 6,and fructokinase, which occurs predominantly in theliver and phosphorylates at carbon I (F ig. 1). G lucoseinhibits the phosphorylation of fructose by hexokinase.In the brain , hexokinase has 20-fold the affin ity for glu-cose it has for fructose. Fructokinase can also catalyzethe phosphorylation of other ketoses, including galacto-


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M ETAB OLIC EFFEC TS O F D IE TA RY FR UC TO SE 2655

heptulose, sorbose, tagatose, and xylulose. Increasingthe amount of fructose in the diets of rats and humansresults in increases in the activity of fructokinase.Fructose-i-phosphate, which accumulates rapidly in theliver, is then cleaved to dihydroxyacetone phosphateand glyceraldehyde by fructose-I-phosphate aldolase(F ig . 1). The deficiency of th is enzyme (fructose-i-phosphate aldolase) results in the most serious of the in-born errors of metabolism involving fructose, which ishereditary fructose intolerance. This defect is charac-terized in children by nausea after consum ing fructose-contain ing foods, usually noted after weaning. It canresult in grow th retardation, liver damage, and evendeath . A ccumulation of fructose-i-phosphate causesdepletion of ATP and inorganic phosphorus and in-creases degradation of nucleotides to uric acid (11).Phosphorus is not available to rephosphorylate ADP .AMP deaminase activity is stimulated by low levels ofphosphorus, resulting in greater degradation of AMPto uric acid (Fig. 2).

Increasing the amount of fructose in the diets of hu-mans and rats increases the activ ity of fructose-i-phos-

Figure 3 . Possible metabolic paths of d ihydroxyacetone phosphate.

phate aldolase. The two trioses formed by the cleavageof fructose-i-phosphate can each follow three paths(Fig. 3 and Fig . 4). 1) Dihydroxyacetone phosphatecan be isomerized to glyceraldehyde phosphate andcontinue through the glycolytic pathway to ultimatelyyield pyruvate, which is converted to either lactic acidunder anaerobic conditions or enters the citric acid cycleas acetyl coenzyme A under aerobic conditions (F ig . 3).The acetyl coenzyme A can then either produce energyvia the respira tory chain or be used as the substrate forfatty acid synthesis. 2) Dihydroxyacetone phosphatemay be reduced to glycerol-3-phosphate and providethe glycerol backbone of synthesized triacyiglycerols,phospholip ids, and other lipids. 3) Dihydroxyacetonephosphate may also be condensed with glyceraldehyde-3-phosphate by aldolase to form fructose-I,6-diphos-phate, and ultim ately glucose or glycogen (the storageform of carbohydrate in the body). Forster (12) hasmeasured glycogen storage in rats infused w ith glucose,fructose, xylito l, and sorbito l. G lycogen deposition wasgreater in animals infused w ith fructose and the twosugar alcohols, xylitol and sorbitol, than in those in-fused w ith glucose. G lycogen synthesis is impaired indiabetics either because glycogen synthase activ ity isinhibited or hepatic glucose uptake and/or glucosephosphorylation are impaired . Because fructose phos-phorylation does not require hexokinase, it m ay over-come the impairment of glycogen synthesis in diabetics.G lycogen synthesis was measured in isolated rat hepat-ocytes from diabetic and normal rats incubated in solu-tions contain ing fructose and/or glucose (13). The pres-ence of fructose stimulated glycogen synthesis enzymesin both normal and diabetic rats, whereas glucose alonefailed to increase either the enzymes or glycogen ac-cumulation in hepatocytes from diabetic rats. The com-bination of the two sugars produced a synergistic in-crease in glycogen accumulation in hepatocytes fromboth normal and diabetic rats. However, studies in-volving isolated hepatocytes may be hard to assess, be-cause metabolism of fructose is not homogeneousthroughout the liver (14). G luconeogenesis from fruc-tose was reported to be much greater in hepatocytes iso-lated from around the portal vein than in those fromthe pericentral regions of the liver lobule (14).


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2656 Vol. 4 June 1990 Th e FASEB j ou r na l HALLFRISCH

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The glyceraldehyde formed from the cleavage offructose-i-phosphate also has three possible metabolicroutes (F ig . 4). 1) It can be phosphorylated by triose-kinase found in the livers of rats, cattle, and guineapigs. This enzyme increases in animals fed fructose andmay be specific for its metabolism . Phosphorylatedglyceraldehyde can continue through glycolysis or beused for gluconeogenesis or glycogen storage. 2) Glyc-eraldehyde may be converted to glycerate and thenenter glycolysis after phosphorylation to 2-phospho-glycerate . G lycerate accumulates in the liver after fruc-to se in fu sio n. 3) Glyceraldehyde fo rmed from fructosemay also be reduced to glycerol by alcohol dehydroge-nase or aldose reductase . G lycerol may be phosphoryl-ated and form a component of triacylglycerols andother lip id compounds or be converted to dihydroxy-acetone phosphate. More fructose is converted to lipidsthan is glucose. Rats fed 66% of their diet as fructosewere more hypertrig lyceridem ic than rats fed 66% glu-cose or laboratory chow for i wk (15). Conversion offructose and glucose to lip ids was also measured in iso-lated human fibroblasts (16). Incubation with 27.5 mMfructose resulted in incorporation of tw ice the amountof lip ids as incubation with 27.5 mM glucose.

CONTROL OF FRUCTOSE METABOLISMA recently discovered form of fructose (fructose-2 ,6-bisphosphate) may serve as an important regulator ofcarbohydrate metabolism in the liver (i7). The synthesisand degradation of fructose-2 ,6-bisphosphate are cata-lyzed by a single enzyme complex (6-phosphofructo-2-kinase/fructose-2 ,6-bisphosphatase). A s in many othersystems, control is a chie ve d by phosphorylation or de-phosphorylation of the enzyme complex, so that whenenergy is needed, carbohydrates are metabolized viaglycolysis, but under anabolic conditions, gluconeogen-esis predom inates. T he level of fructose-2,6-bisphosphateappears to affect the activities of two important regula-tory enzymes controlling carbohydrate catabolism andanabolism in the liver (6-phosphofructo-i-kinase an dfructose-I,6-diphosphatase). The amount of th is fruc-tose compound is regulated by the enzyme complex.Cyclic AMP stimulates fructose-2 ,6-bisphosphatase,which then forms fructose-6-phosphate , lowering the

level of fructose-2,6-bisphosphate. This lowered level offruc tose -2 ,6 -b isp hosp hate stim ulates fru cto se-i,6-dip ho s-phatase, which favors the conversion of fructose-I,6-diphosphate to fructose-6-phosphate, an intermediateof g luconeogenesis . In contrast, an increase in fructose-2,6-bisphosphate stim ulates 6-phosphofructo-i-kinase,which converts fructose-6-phosphate to fructose-i,6-diphosphate, which favors glycolysis. F ructose-2 ,6-bisphosphate has been studied in the liver, muscle, in-testine, and pancreas of m ice and rats, as well as inyeasts. The effect that dietary fructose has on levels offructose-2,6 bisphosphate has not been studied, andmany details concerning its ro le need to be investigatedfurther.

METABOLIC EFFECTS OF DIETARY FRUCTOSEON RISK FACTORS FOR DISEASEIn evaluating human nutrition studies, it is importantto exam ine the actual comparisons being made. Re-sponses to a single dose of fructose may be much differ-ent from responses to a meal containing fructose or toa chronic diet contain ing added fructose. S ince in-div idual differences are usually the greatest source ofvaria tion, the crossover design in which each subjectconsumes a controlled weight-maintain ing diet inwhich one single nutrient is altered during differentperiods is the most powerful design in which to evaluateeffects of that single nutrient. Unfortunately, these ex-perim ents are both expensive and confining for the sub-jects. U sually subjects are given diet counseling, a fewdays of diet records are collected, blood is drawn,weights taken, a supplement may be distributed, andthen measurements are taken again at the end of thestudy. O ften there is no control group. Changes or lackof changes are then attributed to the supplement, whenin fact they could be due to changes in weight, changesin overall composition of the diet due to the addition ofthe supplement, d ifferences in compliance, or a multi-tude of other changes that cannot be assessed. Recentstudies discussed here used a varie ty of designs, varyingamounts of fructose, a w ide range in the length of treat-m ent periods, and compared fructose to no added fruc-tose, other sugars, or complex carbohydrates.GLUCOSE TOLERANCE AND INSULINRESPONSESOwing to the lower acute glucose and insulin responsesto fructose compared w ith other sugars, it has been sug-gested as a replacement for sucrose or glucose for dia-betics (18, 19) and obese people (20). For juvenile orinsulin-dependent diabetes (type i) whose pancreasesproduce no insulin , glucose cannot be transported intomuscle and other tissues to be used for energy, and glu-cose accumulates in blood unless exogenous insulin isin jected . Very high circulating levels of glucose areresponsible for the vascular deterioration that canresult in blindness, neurological damage, and infectionsleading to amputations that often occur in diabetics.For onset of maturity or non-insulin-dependent diabetes


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M ETABO LIC EFFEC TS O F D IETAR Y FR UCTO SE 2659

trol subjects. Approximately 25% of hypertensive sub-jects are reported to have elevated uric acid levels. U ricacid responses after an infusion of fructose were greaterin hypertensive men than in control subjects. Thehyperuricem ia produced after fructose consumptioncould result from increased catabolism of nucleotides,as shown in F ig. 2 , or increased de novo synthesis ofpurines. There is evidence for both theories. A numberof fructose infusion studies have resulted in rapid in-creases in uric acid levels in the blood and urine of chil-dren , normal men, diabetics, and hypertensive andnormotensive subjects (38). Nucleotide content of liverbiopsies decreases after fructose infusion, but not afterglucose infusion. Increased radioactive glycine incorpo-ration into urinary urate after fructose infusion indi-cates increased purine synthesis (39). There are fewstudies reporting uric acid levels after feeding dietaryfructose, but a number of studies have reported in-creases after sucrose diets compared w ith glucose orstarch in men and obese subjects, suggesting that itm ay be the fructose moiety of sucrose that is responsi-ble for the increase (37). A recent crossover study (32)reported elevated uric acid responses to a meal afteradaptation to a fructose-containing diet compared withthe same diet replaced w ith starch. U ric acid levelswere not significantly affected by supplementing self-selected diets in two separate studies involving type 2diabetics (26, 27).

LACTIC ACIDLactic acid is produced as a result of anaerobic glycoly-sis in most mammalian tissues. Extreme elevations causemetabolic acidosis and can result in death (11). M anystudies have shown that more lactate is formed fromfructose than from glucose (37). This increased lactateproduction occurs because fructokinase activ ity is in-creased, the rate-lim iting step for glycolysis (phospho-fructokinase) is bypassed, and pyruvate kinase activ ityis stim ulated by the accum ulation of fructose-I-phosphate .F ructose infusions in humans have resulted in danger-ous increases in blood lactic acid , especially in patientsw ith preexisting acidotic conditions such as anoxia,diabetes, postoperative stress, or urem ia (Ii). D ietaryfructose has also resulted in significant increases in lac-ta te in response to a sugar load in both type I and typeI I d ia be ti cs (40). Lactate increased in another study inwhich the self-selected diets of type II diabetics weresupplemented w ith fructose (27). These lactate levelswere much less dangerous than those that occur afterinfusion, but would not be considered a desirable con-sequence.

SUMMARY AND RECOMMENDATIONSSugars, and particularly free fructose, have increased inthe diets of Americans in the last 15 years. F ructose in-take from caloric sweeteners alone (sucrose, high fruc-tose corn syrup, and honey) accounts for about 8% oftotal calorie intake. A lthough it is possible that under

acute conditions replacement of other sugars such assucrose or glucose with fructose may result in betterglucose and insulin control in type 1 diabetics, there area number of deleterious effects that occur after dietaryadaptation to diets containing substantial amounts offructose, and certain segments of the population thatare more susceptible to these effects. D iets that containfructose in excess of glucose may be malabsorbed bysubstantia l numbers of people and may cause diarrhea.Not enough research has been done to determ ine theeffects of fructose on glycogen deposition in athletes orto determ ine whether it m ay provide a better source ofcarbohydrate under endurance exercise conditions thanother sugars or polysaccharides. A lthough fructosealone is less insulinogenic and glucogenic than equalamounts of glucose or sucrose, when consumed withglucose and after dietary adaptation to a m ixed dietcontain ing fructose, these responses usually are notdifferent from responses after dietary adaptation toother sugars, or are greater than after dietary adapta-tion to complex carbohydrate diets. Insulin sensitivitymay be impaired before changes in fasting glucose orinsulin are altered. Therefore, fructose may be con-sidered no worse than other sugars, but also no better.W ith regard to blood lip ids, there is overwhelm ing evi-dence that fructose increases plasma trig lycerides.Under some conditions, d ietary fructose may cause in-creases in plasma cholesterol. O ther risk factors thatmay be increased in some people include uric acid andlactic acid . A lthough it is v irtually impossib le and cer-ta inly undesirable to consume a fructose-free diet, asfructose is a component of many fruits and vegetables,there is little evidence, except possibly for type I dia-betes, that in a m ixed diet added fructose provides anyadvantage over other sugars. In patients w ith hyperten-sion, obesity , hyperlipidem ia, and gout, it m ay be dis-advantageous to replace other sugars w ith fructose.5j

I would like to thank Dr. Sheldon Reiser for his patience and ad-v ice on the preparation of this manuscript, and D rs. R eubinAndres, R ichard P ratley , and John Sorkin for rev iew ing it.

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