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Use of Alternative Sweeteners in Diabetic Diet Phyllis A. Crapo, RD Alternative sweeteners are widely advocated and used. However, there is insufficient scientific information to determine whether alternative sweeteners are of value in the management of diabetes, either in improving dietary adherance or in contributing to the achievement or maintenance of a lower body weight. Each of the available sweeteners has advantages and disadvantages; no one is preferred. Recommendations about alternative-sweetener use should be tailored to the specific dietary and life-style patterns of the individual. Diabetes Care 11:174-82, 1988 S ucrose, glucose, and foods containing large amounts of the two refined sugars have been restricted in various dietary approaches through- out the history of diabetes therapy (1), particu- larly throughout much of this century, as a means of limiting excursions of blood glucose. (Simple sugars in the form of fruits, vegetables, and dairy products have variably been excluded from this practice.) Conse- quently, alternative sweeteners, both caloric (fructose, sorbitol, mannitol) and noncaloric (saccharin, aspar- tame, cyclamate), have played a dominant role in the provision of sweetness in diabetic diets. Despite this, many questions about their use remain. Are alternative sweeteners actually of any value in the management of diabetes? Do they help people with diabetes adhere to their diabetic diets? Do they help in the treatment of the obesity associated with type II (non-insulin-dependent) diabetes? What are the side effects of the different sweet- University of California, San Diego, Veterans Administration Medical Center, San Diego, California. Address correspondence and reprint requests to Phyllis A. Crapo, RD, Uni- versity of California, San Diego, VA Hospital, V-111G, San Diego, CA 92093. ener alternatives? Are such sweeteners safe? Is there one preferable sweetener? What are the parameters of use that will ensure potential benefit without negative side effects or outcomes? Few of these questions have defin- itive answers that are supportable by research findings. This article outlines the key questions, the available in- formation and research findings, and the apparent con- clusions. Perhaps the first question that should be posed is whether alternative sweeteners are actually of any value in the management of diabetes. Does the availability of alternative sweeteners contribute to adherance to a di- abetic diet or to weight-reduction programs for the in- dividual with type II diabetes? Unfortunately, there are few answers. One survey found that 72% of mothers of diabetic children believed that the use of alternative sweeteners and foods helped their children adhere to their diabetic diets (2). Another survey of 500 people with diabetes found that only 17% felt no craving for sweetness (3). The remaining 83% revealed that if no alternative sweeteners were available, they would use sucrose. In 1977, it was estimated that 91 % of all people with diabetes used saccharin, which reflects a high de- mand for sweetener alternatives (4). However, there are few studies that have investigated the value of nonca- loric sweeteners in improving dietary adherance. One study found no evidence that the use of nonnutritive sweeteners improved adherance to a carbohydrate-re- stricted diet (5). Whether a low- or noncaloric sweetener actually helps in weight reduction is also felt to be ques- tionable. However, there have been a few studies in which covert use of noncaloric sweeteners has been associated with a drop in caloric intake (6,7). Many studies also cite a psychological benefit of noncaloric sweeteners in weight-reduction programs. This claim has not been substantiated but seems to make good sense. 174 DIABETES CARE, VOL. 11, NO. 2, FEBRUARY 1988
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Page 1: Use of Alternative Sweeteners in Diabetic Diet...Use of Alternative Sweeteners in Diabetic Diet Phyllis A. Crapo, RD Alternative sweeteners are widely advocated and used. However,

Use of AlternativeSweeteners in Diabetic Diet

Phyllis A. Crapo, RD

Alternative sweeteners are widely advocated and used.However, there is insufficient scientific information todetermine whether alternative sweeteners are of valuein the management of diabetes, either in improvingdietary adherance or in contributing to the achievementor maintenance of a lower body weight. Each of theavailable sweeteners has advantages and disadvantages;no one is preferred. Recommendations aboutalternative-sweetener use should be tailored to thespecific dietary and life-style patterns of the individual.Diabetes Care 11:174-82, 1988

Sucrose, glucose, and foods containing largeamounts of the two refined sugars have beenrestricted in various dietary approaches through-out the history of diabetes therapy (1), particu-

larly throughout much of this century, as a means oflimiting excursions of blood glucose. (Simple sugars inthe form of fruits, vegetables, and dairy products havevariably been excluded from this practice.) Conse-quently, alternative sweeteners, both caloric (fructose,sorbitol, mannitol) and noncaloric (saccharin, aspar-tame, cyclamate), have played a dominant role in theprovision of sweetness in diabetic diets. Despite this,many questions about their use remain. Are alternativesweeteners actually of any value in the management ofdiabetes? Do they help people with diabetes adhere totheir diabetic diets? Do they help in the treatment of theobesity associated with type II (non-insulin-dependent)diabetes? What are the side effects of the different sweet-

University of California, San Diego, Veterans Administration Medical Center,San Diego, California.

Address correspondence and reprint requests to Phyllis A. Crapo, RD, Uni-versity of California, San Diego, VA Hospital, V-111G, San Diego, CA 92093.

ener alternatives? Are such sweeteners safe? Is there onepreferable sweetener? What are the parameters of usethat will ensure potential benefit without negative sideeffects or outcomes? Few of these questions have defin-itive answers that are supportable by research findings.This article outlines the key questions, the available in-formation and research findings, and the apparent con-clusions.

Perhaps the first question that should be posed iswhether alternative sweeteners are actually of any valuein the management of diabetes. Does the availability ofalternative sweeteners contribute to adherance to a di-abetic diet or to weight-reduction programs for the in-dividual with type II diabetes? Unfortunately, there arefew answers. One survey found that 72% of mothers ofdiabetic children believed that the use of alternativesweeteners and foods helped their children adhere totheir diabetic diets (2). Another survey of 500 peoplewith diabetes found that only 17% felt no craving forsweetness (3). The remaining 83% revealed that if noalternative sweeteners were available, they would usesucrose. In 1977, it was estimated that 91 % of all peoplewith diabetes used saccharin, which reflects a high de-mand for sweetener alternatives (4). However, there arefew studies that have investigated the value of nonca-loric sweeteners in improving dietary adherance. Onestudy found no evidence that the use of nonnutritivesweeteners improved adherance to a carbohydrate-re-stricted diet (5). Whether a low- or noncaloric sweeteneractually helps in weight reduction is also felt to be ques-tionable. However, there have been a few studies inwhich covert use of noncaloric sweeteners has beenassociated with a drop in caloric intake (6,7). Manystudies also cite a psychological benefit of noncaloricsweeteners in weight-reduction programs. This claim hasnot been substantiated but seems to make good sense.

174 DIABETES CARE, VOL. 11, NO. 2, FEBRUARY 1988

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PA. CRAPO

Despite the lack of research demonstrating a definitebenefit for dietary adherance or for weight reduction,many educators feel that the availability of alternativesweeteners is beneficial, even if only for psychologicalreasons; i.e., the patient feels that he/she can follow adiet better with an alternative source of sweetness (8).

Note that questions have been raised in recent yearsabout whether the avoidance of sucrose really facilitatesmetabolic control (9-14). Nevertheless, most cliniciansand health professionals, as well as official AmericanDiabetes Association policy (15), recommend some de-gree of limitation of sucrose in the diet. In addition,there are various reasons, not always directly related todiabetes, why an individual might choose to use an al-ternative sweetener. These include the desire or need toincrease the micronutrient and/or fiber level of the dietfor a particular calorie level while maintaining palata-bility, to decrease the incidence of dental caries, to con-trol serum lipid levels, and even, for some, to improvetaste.

AVAILABLE ALTERNATIVE SWEETENERS

Several alternative sweeteners are available for use byindividuals with diabetes. They are generally catego-rized as caloric (nutritive) or noncaloric (nonnutritive)(Table 1).

IDEAL ALTERNATIVE SWEETENER

The ideal alternative sweetener for diabetes would notraise blood glucose levels, would taste good, would beeasy to use, would be inexpensive, would have the rightconsistency for various food uses, would be chemicallystable, would have minimal or no side effects, wouldnot raise blood lipid levels, would be completely safe,and would contain no calories. Unfortunately, none ofthe available sweeteners meet all of these criteria. Thereis no preferred sweetener. Consequently, the health

TABLE 1Available alternative sweeteners

Caloric

FructoseSugar alcohols

Sorbitol*Mannitol*Xylitol*t

Noncaloric

SaccharinAspartame*Cyclamatet

*Used primarily in food production.tUse currently restricted or banned within the United States.^Although aspartame is chemically caloric (or nutritive), it is -200times as sweet as sucrose, so very little is required to attain equivalentsweetness. Thus, when used in manufactured products (as Nutra-Sweet), it contributes virtually no calories. For pourable tabletop use(Equal), it is packaged with a buffer, such as dextrose or lactose, whichprovides small amounts of calories.

professional must have a clear understanding of the ad-vantages and disadvantages of each sweetener alterna-tive and must examine and assess the life-style, dietarypatterns, and potential risks of individuals so that advicecan be tailored to specific needs and concerns.

CALORIC SWEETENERS

Fructose. Fructose (levulose or fruit sugar) is a commonmonosaccharide in nature, found in its free form in honey,in fruit and other plants, and in combined form as halfof the disaccharide sucrose. It traditionally was scarce,but technological advances in the late 1960s and early1970s made large-scale economical production possi-ble, and fructose is now being marketed more actively.

Fructose probably is the sweetest of the naturally oc-curring sugars, being —1.0-1.8 times as sweet as su-crose (16). The actual sweetness depends on the con-centration, pH, and temperature of the tasting medium.It is sweeter when cool, dilute, and at a more acidic pH(17). Even though its caloric content is the same as othernutritive sugars (4 kcal/g), fructose provides the possi-bility of caloric reduction at equal sweetness because ofits great sweetening potential. However, when Hardyet al. (18) incorporated fructose into sugar cookies, whitecake, and vanilla pudding, it was not determined to besweeter than sucrose, and indeed sucrose was fre-quently ranked significantly sweeter than fructose (18).When they decreased the sugar level in these products,flavor and overall acceptance ratings also decreased.Thus, when fructose is incorporated into mixed foods,the theoretically potential caloric reduction is not al-ways achieved. Still, in specific food applications, ca-loric savings can be accomplished. The caloric savingsare not usually as great, however, as those achievableby foods formulated with noncaloric sweeteners (suchas aspartame or saccharin).

Foods sweetened experimentally with pure crystallinefructose resulted in significantly lower serum glucoseand insulin responses than sucrose-sweetened productsin adults with type II diabetes (19). However, pure crys-talline fructose is expensive, so manufacturers usuallyuse one of the high-fructose corn syrups (HFCSs) con-taining varying amounts of fructose (42, 55, or 90%),the remaining carbohydrate predominantly being glu-cose with a small percentage of higher saccharides (20).HFCSs supplied for a study as 90% fructose had an effecton blood glucose similar to that of sucrose (21,22).However, analysis of the syrup indicated that it was only75.8% fructose. Although difficult to explain, the studyresults indicate that HFCSs with a fructose-to-glucoseratio of 75:25 are unlikely to differ from sucrose (witha fructose-to-glucose ratio of 50:50) in terms of bloodglucose effect. Thus, there may be no benefit of a foodsweetened with an HFCS compared with a food sweet-ened with a noncaloric sweetener that has no glucose-raising effect or extra calories.

Fructose is absorbed from the intestine more slowlythan glucose (23) and then predominantly and rapidly

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is taken up and metabolized in the liver (24). It entersthe cell and is metabolized independently of insulin tothe triose phosphate and, subsequently, via glyconeo-genesis to glycogen. In the absence of adequate insulin-ization, the trioses enter the gluconeogenic pathway toform glucose. Therefore, in insulin deficiency, increasedglucose production can result from these trioses, whereasin treated diabetic and nondiabetic individuals, littlegluconeogenesis from fructose occurs (25). Acutely,fructose has less influence on blood glucose level thandoes glucose, sucrose, HFCSs, or many complex car-bohydrates in diabetic and nondiabetic individuals (26-29). However, when basal plasma glucose levels ex-ceeded 140 mg/dl in one study, fructose caused post-prandial plasma glucose excursions comparable to thosewith sucrose or HFCS (22). In another study of subjectswith basal plasma glucose levels >140 mg/dl, fructosemaintained a significantly lower blood glucose responsethan glucose and sucrose, although it was increasedcompared with blood glucose response to fructose innondiabetic subjects and subjects with impaired glucosetolerance (29). Fructose also has a smaller influence oninsulin secretory response than does glucose or sucrose(27,29,30).

Pelkonen et al. (31) found no change in fasting bloodglucose, glycosuria, or diurnal blood glucose levels inadult type I (insulin-dependent) diabetic patients when75 g of starch was replaced by fructose for several weeks,regardless of whether diabetes control was excellent orpoor at the beginning of the experiment. Crapo et al.(32) found reduced postprandial hyperglycemia to anoral glucose challenge and to fructose-containing mealscompared with sucrose-containing meals after 14 daysof fructose feeding in the diet of type II diabetic individ-uals without change in insulin response. Type I diabeticsubjects did not have a change in glycosuria when fruc-tose (1.5 g/kg body wt) was substituted for starch fortwo separate 1-wk periods (33). An earlier study in chil-dren had shown no insulin-sparing effects when abouthalf the daily carbohydrate for 5 wk was fructose ratherthan isocaloric glucose or sucrose (34). Neither study inyoungsters with type I diabetes demonstrated a deteri-oration in control of diabetes with fructose ingestion,nor was there a marked improvement. It was suggestedthat fructose in amounts up to 0.5 g • kg"1 • day"1 wouldhave no deleterious effects in type I diabetic children ingood or fair control, providing the child adhered to aquantitative diet, the fructose was used on an isocaloricbasis, and the fructose was used with parental supervi-sion (33).

Other questions about the use of fructose are alsoraised. Serious side effects of fructose are seen whenfructose is administered intravenously at high doses.However, there are no significant side effects, e.g., in-creased blood levels of urea, lactate, pyruvate, or bili-rubin, seen after oral ingestion of fructose (32,35,36).Large (>50 g) single oral doses of fructose may lead todiarrhea or gastrointestinal symptoms in some individ-uals (37).

Another, potentially adverse, side effect of fructose isits effect on triglyceride levels. It has been implicatedas the component of sucrose responsible for elevationof plasma triglycerides (38,39), and this suggestion hasbeen supported by studies in animals and in hypertri-glyceridemic (32,40,41), hyperinsulinemic (42), dia-betic (43), and normal (44) subjects, in which fructosefeeding (40-300 g/day) led to hypertriglyceridemia. Otherstudies have found that ingestion of fructose (33-154g/day) in normal (35,36,45), diabetic (44), and hyper-triglyceridemic (46) subjects did not produce an in-crease in fasting triglyceride level. It has been suggestedthat the hypertriglyceridemic effect of dietary carbohy-drate is mild and temporary in nature and that triglyc-eride levels will return to baseline levels with time (46-48). Longer-term studies of fructose feeding are neededto confirm this. Until such evidence is available, fruc-tose ingestion in subjects with preexisting hypertriglyc-eridemia should be approached with some caution andmonitoring. No increases in cholesterol levels have beenreported after fructose feeding in humans except in hy-perinsulinemic subjects.Sorbitol and mannitol. Sorbitol and mannitol are poly-alcohols, or sugar alcohols, obtained commercially fromthe reduction of either glucose or fructose. Both occurnaturally in plants and have sweetening effects similarto that of glucose and about half that of sucrose (16).Each contains 4 kcal/g, the same amount as the hexosesfor which they might be substituted. They are absorbedslowly from the gastrointestinal tract (49) and have lessinfluence on blood glucose and insulin levels than glu-cose, sucrose, or fructose. They are rapidly taken upand converted to fructose in the liver. In insulin defi-ciency, sorbitol and mannitol can be converted to glu-cose. The slow passive absorption of sorbitol and man-nitol can cause osmotic diarrhea, abdominal gas,discomfort, and malabsorption even with relatively loworal doses (usually stated as 30-50 g, although someindividuals have tolerance levels as low as 10 g). Thiseffectively limits consumption. Their low level of sweet-ness also limits their usefulness. Diabetic children havebeen shown to tolerate dietary sorbitol (as much as 41g/day in divided doses), with only minor intestinalsymptoms in a few of the children, with no increase inblood glucose levels or glycosuria, and with no increasein insulin requirements (50).

Note that dietary or exogenous sorbitol does not ac-cumulate in the lens or any other body tissue. Absorbedexogenous sorbitol and other sugar alcohols are re-moved from the blood and metabolized by the liver. Inaddition, even when high plasma levels of sorbitol areachieved, there is poor diffusibility of the sugar alcoholsinto cells of the lens or through other biologic mem-branes (51).Xylitol. Xylitol is a naturally occurring sugar alcohol thatis obtained by hydrogenation of xylose, which is pro-duced from xylan-containing plant materials. It is a pal-atable sweetener with a sweetness equivalency similarto fructose in an aqueous solution. Like fructose, its

176 DIABETES CARE, VOL. 1 1 , NO. 2, FEBRUARY 1988

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P.A. CRAPO

sweetness varies with changes in physical state, i.e.,reduced by warming or by addition of fruit acids. Likethe other sugar alcohols, it contains ~4 kcal/g but isslowly absorbed (52), resulting in little influence on bloodglucose and insulin levels. The slow absorption of xylitolcan be a disadvantage (as it is with sorbitol and man-nitol), because osmotic diarrhea and flatulence may oc-cur after administration of doses in the range of 30-40g. When given in incremental doses over a period ofweeks, xylitol has been shown to be tolerated at levelsof up to 90 g/day (53,54). No significant side effects,e.g., increased blood levels of urea, lactate, insulin,pyruvate, triglycerides, or bilirubin, have been shownto occur after oral administration (35). Total or partialreplacement of sucrose by xylitol has been shown tomarkedly reduce dental caries (55); therefore xylitol hasa preferred use in foods that are sticky and adhere toteeth and thus are likely to be more cariogenic. Thissugar has been successfully used in Scandinavian coun-tries in chewing gums. However, chronic intake of xy-litol in animals has been shown to be associated withtumor induction and other pathology. Consequently, useof xylitol is currently curtailed in the United States, andno recommendation concerning its use can be made.

Diabetes educators should be aware that foods for-mulated with sugar alcohols may contain energy valuesequal to or greater than that of a nondietetic counterpart.To achieve the same smooth texture in dietetic cookies,ice cream, chocolate, and candies as that of comparableproducts, manufacturers may need to increase fat con-tent. In addition, because of their low level of sweet-ness, greater quantities of sorbitol or mannitol may beneeded in certain products to achieve equivalent sweet-ness. Either way, the effect is one of increasing the ca-loric content of the final product. Whereas sorbitol andmannitol are acceptable sweeteners for individuals withdiabetes, there are other sweetners that offer equivalentadvantages without as many disadvantages. Thus, thesugar alcohols are not the sweeteners of choice.

NONCALORIC SWEETENERS

Aspartame. Aspartame is actually a nutritive proteinsweetener produced commercially from two amino acids,the methyl ester of L-phenylalanine and L-aspartic acid.It is marketed under the trade name NutraSweet in foodproducts and Equal as a tabletop sweetener by the man-ufacturer (Searle). It was approved by the Food and DrugAdministration (FDA) for use as a food additive in 1981and for use in other products, including soft drinks, in1983. It is digested as a protein, and like other proteinsprovides 4 kcal/g (56). Because it is 180-200 timessweeter than sucrose, only very small amounts are neededto achieve equivalent sweetness, and consequently itscaloric contribution to a food is usually minute and in-significant. Aspartame is more expensive (4-5 times)than saccharin but has a taste considered to be excellent(57). It is not a universal sugar substitute because it breaksdown with prolonged heating into its constituent amino

acids with resulting loss of sweetness. Consequently, itcannot be used in food applications requiring prolongedheat unless special procedures are employed, such asadding it after heating. Although relatively stable in solidform, aspartame has poor stability in liquids (58); there-fore, liquid foods containing aspartame must be care-fully formulated and stored. Aspartame cannot be usedin recipes that require a bulk of sugar unless other func-tional compensations are made.

Aspartame does not alter glycemic control of diabetes(59). The main concerns that have been raised aboutthe use of aspartame have been those of safety. Individ-uals with diabetes are not felt to differ in this regardfrom individuals without diabetes. Safety has not beenestablished for individuals <2 yr old, but use should beminimal in this age group. The basic safety concerns areoutlined below.

1. Various mild nonspecific symptoms, including diz-ziness, headache, and menstrual irregularities, have beenassociated with ingestion of aspartame (60). No sci-entific evidence to date suggests that such episodes areanything but coincidental. After evaluation of >500complaints, the Centers for Disease Control (CDC; 60)ruled that data did "not provide evidence for the exist-ence of serious, widespread, adverse health conse-quences attendant to the use of aspartame" and it isunlikely that the results of diabetic individuals woulddiffer in this regard. The reported symptoms were mildand were common in the general population. This reportdid not rule out the possibility that certain individualsmight have an unusual sensitivity to the aspartame-sweetened products.

2. Biproducts of metabolism of aspartame, methanol,and diketopiperazine are toxic. About 10% by weightof aspartame is converted to methanol, which occurseither before consumption through improper storage ofan aspartame-sweetened product or internally duringmetabolism of aspartame (58). Either way, the dose ofmethanol is the same. If conversion occurs before inges-tion, the result is a marginally acceptable, but not un-safe, product. Other foods (fruits, vegetables, beer, andwine) are also sources of methanol in the diet in amountsequal to or greater than those seen with significant as-partame use. Whereas few data are available on meth-anol toxicity, it appears to be due to formaldehyde, whichis formed while methanol is metabolized and is con-verted to formic acid, leading to accumulation of for-mates (61). Clinical studies have found no measurableblood levels of methanol with loading doses of aspar-tame at the projected 99th-percentile exposure level of34 mg/kg (62). Abuse doses of 200 mg/kg of aspartamehave not been shown to increase blood formate con-centrations over predosing levels (62). The FDA hasconcluded that there is no cause for concern from thelevels of dietary methanol resulting from the highestprojected levels of aspartame ingestion. Any concern ofthe possible toxic effects of diketopiperazine were elim-inated by long-term animal studies (63).

3. Aspartame might alter brain neurotransmitter ac-

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ALTERNATIVE SWEETENERS IN DIABETIC DIET

tivity resulting in functional or behavioral changes. Ithas been suggested that when aspartame is ingested inconjunction with a high-carbohydrate diet, neurochem-ical changes due to the elevation of aromatic aminoacids, including phenylalanine, may lead to behavioralchanges, particularly in children (64). Aspartame intakein rats at doses of 200 mg/kg body wt significantly in-creases brain phenylalanine and tyrosine levels (precur-sors of adrenergic neurotransmitters such as norepi-nephrine and dopamine; 65,66) while decreasing brainlevels of leucine, isoleucine, and valine. Simultaneousingestion of carbohydrate has been reported to poten-tiate these effects while blocking the increases in braintryptophan, 5-hydroxyindoleacetic acid, and serotoninnormally seen after a carbohydrate meal (65). Recentstudies have found significant increases in neurotrans-mitter concentrations in critical brain regions (particu-larly the hypothalamus) rich in neurotransmitters afteraspartame ingestion at levels of 130 and 650 mg/kgbody wt by mice (67), although previous studies hadfound no apparent alteration in whole-brain concentra-tions of neurotransmitters in rats fed aspartame at levelsup to 200 mg/kg body wt (66). These issues were con-sidered before the approval of aspartame for use in car-bonated beverages. After reviewing all of the availabledata, the FDA concluded that, although aspartame in-creased plasma and brain phenylalanine levels, therewas no evidence that aspartame, either alone or in com-bination with dietary carbohydrates, altered neurotrans-mitter activity or behavior (68).

4. Aspartame use might lead to brain tumors or neu-rotoxicity. In keeping with the requirements of the FDA,data from chronic feeding studies in mice and rats weresubmitted to the FDA (69,70), and the FDA commis-sioners concluded that aspartame and its products donot contribute to brain tumor formation in rats (71). Thepossibility that the amino acids phenylalanine and as-partic acid, either alone or in combination with gluta-mate, might result in brain damage, mental retardation,or endocrine dysfunction has also been reviewed. Suchneurotoxicity had been shown for glutamate, which likeaspartate is a dicarboxylic amino acid, and the effectsof glutamate and aspartate may be additive. Glutamateis in widespread use in food, particularly as monoso-dium glutamate (MSG). Toxicity has been demonstratedprimarily in mice (72,73); in normal humans, controlledstudies of aspartame alone and aspartame plus MSGingestion at expected and abuse levels of consumptionshowed no effect of aspartame on plasma concentra-tions of aspartate and glutamate beyond those arisingfrom MSG contained in the meals themselves (74-78).The FDA concluded there is no evidence that the inges-tion of aspartame, either alone or together with gluta-mate, contributes to brain damage or dysfunction ofneuroendocrine regulatory systems (71).

5. Long boiling of aspartame produces an "unnatu-ral" version of aspartame. In this process, known asamino acid racemization, the amino acids are convertedto their d-isomers (79). No one knows the potential health

consequences of ingesting this altered form of the chem-ical. However, the major use problem of aspartame isthat it loses sweetness when heated and should not besubjected to long-term boiling. The only practical im-plication is that of educating the public about the properhandling and storage of aspartame.

6. Harm to people with inherited phenylketonuria(PKU). Sustained plasma levels of phenylalanine result-ing in PKU are associated with mental retardation. Thequestion was raised initially as to whether aspartame usecould raise plasma phenylalanine levels sufficiently tocause mental retardtion similar to that seen in PKU.Clinical studies demonstrated, however, that aspartameuse could not be expected to increase the incidence ofthe form of mental retardation associated with sustainedelevation of plasma phenylalanine levels (71,74-77,80-83). It was concluded that the marketing of aspartamewould not create any additional risk to PKU childrennot on a restricted diet, individuals heterozygous forPKU, undetected cases of PKU, or pregnant women withthe special condition hyperphenylalaninemia (71).

The FDA has set 50 mg/kg body wt as an acceptabledaily intake (ADI) for aspartame. This is — 1 % of anamount shown in animals to have no toxic effects.(The Canadian and FAO/WHO ADI is set at 40mg/kg.) Thus, the ADI indicates that an intake of aspar-tame at 50 mg • kg"1 body wt • day"1 over a lifetime isconsidered safe by a factor of at least 100-fold. For a50-kg individual, an ADI of 50 mg/kg represents 1212-oz cans of 100% aspartame-sweetened soda or -62cans of soda sweetened with a blend of aspartame plussaccharin (Table 2). One packet of Equal granulatedsweetener contains 35 mg of aspartame, which is equiv-alent in sweetness to 2 tsp of sucrose. An ADI of 50mg/kg would allow 71 packets of Equal for the 50-kgindividual. It has been estimated that 34 mg/kg (equiv-alent to ~1 Equal packet/kg body wt) represents the 99thpercentile of the projected intake for an entire day whenaspartame replaces all dietary sucrose and saccharin ona sweetness basis (71). Because aspartame cannot re-place all sources of dietary sucrose and saccharin, thisestimate represents an exaggerated estimate of intake,and consumption figures remain well below the ac-ceptable daily intake level.

In summary, aspartame has been determined and re-affirmed in ongoing evaluation by the FDA and otherregulatory agencies to be safe for healthy adults, lactat-ing or pregnant women, children and adolescents, andpeople with diabetes.Saccharin. Discovered in 1897, saccharin was the firstman-made sugar substitute. It gained widespread pop-ularity during the sugar shortages of the First and SecondWorld Wars, and when cyclamate was banned in 1970,it became the only available noncaloric sweetener. It is300-400 times as sweet as sucrose and has essentiallyno caloric value, but it does have a bitter aftertaste foundto be objectionable by some people. It is the least ex-pensive of the alternative sweeteners and can be usedin cooking, although it does not provide the functional

178 DIABETES CARE, VOL. 11, NO. 2, FEBRUARY 1988

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P.A. CRAPO

TABLE 2Acceptable daily intake (ADI; 50 mg/kg) of aspartame

Children

Males

Females

Age (yr)

1-34-67-10

11-1415-1819-76

11-1415-76

kg

132028

456670

4655

Weight

Ib

294462

99145154

101120

ADI (mg)

65010001400

225033003500

23002750

Cans of soda*(n rounded down)

357

111617

1113

Packets of Equalt

182840

6494

100

6578

•One 12-oz can of 100% aspartame-sweetened soda (U.S. figures) containstOne packet of Equal contains 35 mg aspartame.

-200 mg (170-200) aspartame.

(bulk) qualities of the caloric hexoses. In April 1977, theFDA proposed a ban on saccharin as a food additivebecause it had been found to cause urinary bladder can-cer in experimental animals. The major scientific evi-dence for the proposed ban were two-generation studiesin rats, in which the second-generation male animals,exposed to saccharin in utero and throughout remaininglife, developed bladder carcinoma at saccharin doses of^ 5 % (84-86). Because of an intense public responseagainst the proposed ban, Congress instituted a mora-torium that postponed the ban for 18 months (Publ. Law95-203, The Saccharin Study and Labeling Act) to allowfor further research and assessment of the issue. Thismoratorium on the saccharin ban has been extended onfour subsequent occasions, the most recent being in April1985. This legislation required specific warnings on la-bels of foods containing saccharin stating that "use ofthis product may be hazardous to your health. Thisproduct contains saccharin which has been determinedto cause cancer in laboratory animals."

A select committee on sugar substitutes of the Amer-ican Diabetes Association, chaired by Ronald K. Kalk-hoff, MD, reviewed the experimental data on saccharinavailable through May 1978 and concluded that "basedon evidence now available, there appears to be littlejustification for placing further governmental restrictionson the use of saccharin by the American public at thepresent time" (87). Subsequently, additional researchevidence from epidemiological studies in humans havefound no association between bladder cancer risk anda history of consumption of artificial sweeteners (88-90). However, such studies are felt to lack the sensitivityto detect relatively weak carcinogens. Studies in animalshave shown dose-response relationships and have con-firmed that large doses of saccharin (4-5% or above)are associated with a slightly higher incidence of blad-der cancer in male rats than in control animals, evenwithout in utero exposure. The National Academy ofSciences (NAS) concluded in 1978 that saccharin wasa carcinogen in animals, although of low potency, and

that it was a potential cancer-causing agent in humans(91). Although there is inadequate evidence to provethat saccharin is not a carcinogen in humans, there isessentially no argument that, if anything, it is a veryweak carcinogen. Current food laws do not require adetermination of benefit or efficacy of alternative sweet-eners, and essentially no studies are available. In thepast, the FDA's interpretation of the Delaney Clause ofthe 1958 Food Additives Amendment to the Federal Food,Drug, and Cosmetic Act of 1938 has been strict. Theamendment states that "no additive shall be deemed tobe safe if it is found to induce cancer, when ingestedby man or animal. . . ." In the past few years, the FDA'sinterpretation of the Delaney Clause appears to bechanging, moving to the calculation and assessment ofquantitative risk. Public interest groups continue to ar-gue, however, that no level of risk is acceptable, par-ticularly when an alternative is available.

Subjects who may be at higher-than-normal risk fromartificial-sweetener ingestion include children and preg-nant women, because the effective dose to the childor fetus may be greater than in other groups. There isno evidence, however, of harm to the fetus frommaternal saccharin ingestion. Because other alterna-tive sweeteners are available, the consumer has a per-sonal choice. Safe limits of intake of saccharin have notbeen defined by the FDA. The ADI suggested by theFAO/WHO is 0-2.5 mg/kg, which is only achievablewhen other alternative sweeteners are also available.Previous GRAS (Generally Recognized As Safe) list rec-ommendations (1955) were for limitations of saccharinto 0.5 g/day in children and ~1 g/day in 70-kg adults(National Academy of Sciences/National ResearchCouncil, NAS/NRC). [One teaspoon of packeted pour-able saccharin (which includes a carrier) contains in therange of 14-20 mg of saccharin.] Recommended limi-tations on daily intake of saccharin should be devel-oped.Cyclamates. Cyclamate was discovered in the 1940s,and because it lacked the bitter aftertaste of saccharin,

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ALTERNATIVE SWEETENERS IN DIABETIC DIET

it became widely used in the United States, particularlyin soft drinks. In 1970, however, on the basis of a reportfrom rat studies that large doses (given with saccharin,10:1) were associated with increased risk of bladdercancer (92), cyclamate use was banned by the FDA. Onmore than one occasion, Abbott Laboratories has peti-tioned the FDA to reassess the status of cyclamates. Mostrecently, in response to a 1982 petition, the Cancer As-sessment Committee of FDA reviewed all cyclamate dataand concluded that the collective weight of the manyexperiments intending to discriminate between the car-cinogenicity and noncarcinogenicity of cyclamate in-dicate that cyclamate is not carcinogenic (93). A com-mittee on carcinogenicity of cyclamates was thenestablished by the NAS/NRC at the request of the FDAto study the question. This committee also concludedthat cyclamate did not cause cancer but suggested thatthe FDA conduct further research to rule out the possi-bility that cyclamate could promote cancer when usedwith saccharin or other substances. The FDA is nowevaluating that possibility as well as reports that thesweetener is associated with testicular atrophy and chro-mosomal damage. Although cyclamate continues to beavailable in Canada, no recommendations can be madefor its use in the U.S. because it is still banned. Its avail-ability would provide consumers with an additionalsweetener choice, one that was well accepted by thepublic before its ban.

REFERENCES

DISCUSSION

In conclusion, there is insufficient scientific infor-mation to determine whether alternative sweet-eners are of value in the management of diabetes,either in improving dietary adherance or in con-

tributing to the achievement or maintenance of a lowerbody weight. Despite this uncertainty about the efficacyof their use in dietary treatment, alternative sweetenersare widely advocated and used. Consequently, the healthprofessional must be prepared to provide advice abouttheir use. Of the available alternative sweeteners, noneis preferred. Each has advantages and disadvantages.Recommendations about alternative-sweetener use shouldtherefore be tailored to the specific dietary and life-stylepatterns and concerns of the individual.Research needs. /) Does use of alternative sweetenerscontribute to diabetes control and/or to the achieve-ment and/or maintenance of lower body weight in obesepeople? 2) What are the risks and metabolic effects oflong-term individual and combination alternative sweet-ener use in humans, particularly in individuals with di-abetes because their intake of alternative sweeteners asa group may be greater than population means? 3) Doglucose and sucrose need to be restricted in the diets ofindividuals with diabetes in comparison with the dietsof the nondiabetic population?

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