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How Sweet It Is: Sweeteners in Health and Disease
Edward Saltzman, M.D.

Dr. Saltzman is Assistant Professor of Medicine, Tufts University School of Medicine, and Scientist II, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.

Dr. Saltzman reports no commercial conflicts of interest.


Release Date: 02/14/2006
Termination Date: 02/14/2009

Estimated time to complete: 1 hour(s).

Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
 
Learning Objectives
Upon completion of this Cyberounds®, you should be able to:
  • List the categories and types of nutritive and nonnutritive sweeteners
  • Discuss the relative contraindications for patients to consumption of classes of sweeteners and specific sweeteners
  • Counsel patients on the general risk and benefits of sweeteners, based on present scientific knowledge.

 
Any opinions, findings, conclusion or recommendation expressed in this publication are those of the author and do not necessarily reflect the views of the U.S. Department of Agriculture.
...Wars have been fought over sugar.

We like foods that taste sweet. Wars have been fought over sugar, people have been enslaved over sugar and sugar has played large roles in national economies.(1) Preference for sweet taste is innate and is observed in infants. The degree to which individuals prefer sweet taste appears to vary because of factors such as genetic differences in taste receptors, age and exposure to sweet foods.(1),(2)

Nutritive v. Nonnutritive

Substances that impart sweet taste can be broadly classified as nutritive or nonnutritive. Nutritive sweeteners provide energy, usually as carbohydrates, while nonnutritive sweeteners provide negligible or no energy. Nutritive sweeteners include:

  1. monosaccharides such as glucose, galactose or fructose;
  2. disaccharides such as sucrose, maltose and lactose;
  3. longer chain carbohydrates such as oligosaccharides and polysaccharides;
  4. sugar alcohols (polyols), which are derived from carbohydrates but are generally not absorbed completely in the small intestine.
Nonnutritive sweeteners include:
  1. monosaccharides or disaccharides that have been modified to prevent absorption or utilization as energy;
  2. amino acid molecules that have sweet taste;
  3. novel or non-macronutrient molecules.
The term "sugars" includes all monosaccharides and disaccharides,and the term "sugar" may refer specifically to sucrose.

Nutritive and nonnutritive sweeteners are considered food additives and are subject to approval by the U.S. Food and Drug Administration (FDA) by one of two mechanisms. Additives may be classified as generally recognized as safe (GRAS), based on experience prior to the 1958 Food Additives Amendment, or by petitioning the FDA for approval as GRAS. Most sugars are considered classified as GRAS, as are some sugar alcohols and novel sugars (see Table 1 below).

Table 1. Non-Sugar Sweeteners.*

  Dietary Energy
(Kcal/gram)
FDA Status
Sugar Alcohols
Sorbitol 2.6 GRAS
Mannitol 1.6 Approved
Xylitol 2.4 Approved
Erythritol 0.2 GRAS
Novel Sugars
D-Tagtose 1.5 GRAS
Trehalose 4 GRAS
Nonnutritive Sweeteners
Aspartame 0 Approved
Acesulfame-K 0 Approved
Saccharin 0 Approved
Sucralose 0 Approved
Neotame 0 Approved

*Adapted from (3).

The other mechanism is approval under the Food Additives Amendment, which dictates testing for immediate and long-term health effects, toxicity, teratogenicity and carcinogenicity. Nonnutritive sweeteners are generally approved by this method. When approved as a food additive, the FDA may propose a level at which there would be no toxicity, called the acceptable daily intake or ADI. The ADI is a conservative level and is approximately 100 times less than the levels at which no toxicity has occurred in studies.(3)

...Nutritive and nonnutritive sweeteners are considered food additives and are subject to approval by the FDA.

Measuring Consumption

Consumption of sweeteners is most often assessed by two methods. The first method is an estimate of consumption of large populations or nations. Determination of the overall food item(s) available to a population is estimated by production and release, and is then adjusted for anticipated waste and spoilage. This method is usually described as either "food availability" or as "food disappearance".

The other method by which consumption is measured is by survey of large numbers of persons or populations, although measurement is conducted in far fewer individuals than could be assessed by food availability methods. Food intake data are generated by national or large surveys by use of dietary recalls or food frequency questionnaires. In general, disappearance data overestimate consumption, while survey data underestimate consumption.

According to food disappearance data from the U.S. Department of Agriculture (USDA), our consumption of nutritive sweeteners has increased approximately 20% over the last three decades (see Figure 1 below). In 2001 the average per capita added nutritive sweetener consumption was 31 teaspoons/day. The estimated percent of total dietary energy derived from sweeteners was 18%. Over the same period, there was a 35% decrease in cane and beet sugars, while corn sweeteners increased by 40% per cent. High fructose corn syrup was introduced commercially in the 1960s and is the product of enzymatic conversion of cornstarch to glucose and fructose, in proportions of 42%, 55% or 90% fructose. In the U.S., the majority of high fructose corn syrup is consumed in soda and fruit drinks.

Survey data from the Continuing Survey of Food Intakes by Individuals (CSFII) and the National Health and Nutrition Examination Survey (NHANES) reveal trends similar to disappearance data. In 1994-1996, caloric intake from added sweeteners as a percent of total energy intake was 16%,(4) and sweeteners from soft drinks and fruit drinks accounted for almost one-third of total daily sweetener intake. Interestingly, the percentage of dietary energy derived from sweeteners decreased from 21% in the 1988-1994 survey to 16% in the later survey. Large differences in sweetener consumption were noted among age, gender and ethnic groups. For example, the highest consumption levels were observed in adolescents (20% of energy intake) and particularly among girls age 14-18 years, 10% of whom consumed over 35% of calories from added sweeteners.

Figure 1. Estimated Per Capita Sweetener Consumption, Total and By Type of Sweetener, 1966-2004.

Figure 1

Source: USDA.

Our consumption of nutritive sweeteners has increased approximately 20% over the last three decades.

Do Sweeteners Cause Obesity?

Alarming increases in the prevalence of obesity occurred at the same time as increases in sweetener consumption, prompting investigations to determine if intake of sweeteners leads to development of obesity. Epidemiologic evidence linking consumption of both nutritive and nonnutritive sweeteners provides mixed results. In some surveys, consumption of sweetened soft drinks such as soda has been associated with overweight (cross-sectional surveys) and gains of weight (longitudinal surveys).(5),(6) However, other surveys have found no relationship between sweeteners and energy intake, body weight or obesity.(7)

Few intervention studies have been conducted to determine if replacement of added sugars with either complex carbohydrates or nonnutritive sweeteners could influence body weight. In two trials where subjects were trying to reduce weight, recommendations were provided to consume foods with or without aspartame.(8),(9) No significant differences in weight loss were observed, although long-term maintenance of lost weight was better in the group consuming foods with aspartame. In subjects consuming weight loss diets where sugars were replaced with complex carbohydrates, no advantages were found.(10) Based on these limited studies, it appears that replacement of nutritive sweeteners with nonnutritive sweeteners or complex carbohydrates does not confer significant advantages for weight loss.

In contrast, trials where subjects consumed diets ad libitum, replacement of sucrose or high fructose corn syrup with nonnutritive sweeteners or with complex carbohydrates resulted either in less weight gain or reductions in weight.(10) Sweetened beverages, such as soda or fruit drinks, may be of particular concern because excess intake of calories from liquids may be more poorly regulated than from solids. Research suggests that when excess energy is provided in liquids, we do not adjust our intake of other foods very well to compensate for the liquid calories.(11) In contrast, when excess energy is provided as solid food, we better (but not completely) compensate by reducing our subsequent intake to account for the earlier calories.

Sugars and Health

In the 2002 Institute of Medicine's Dietary Reference Intakes, an upper limit on sugar intake could not be established because of insufficient proven relationships between intake of sugars and development of diabetes, cardiovascular disease, dyslipidemia, obesity, dental caries and behavioral problems. It was noted that intake of sugars or simple carbohydrates may contribute to hypertriglyceridemia in susceptible individuals. An upper limit for added sugars of 25% of dietary energy was established because diets with added sugar greater than this level may contain lower amounts of several minerals or vitamins.(7)

Fructose: Especially Harmful?

The increase in fructose intake, in large part associated with increased intake of high fructose corn syrup, has raised concern about some specific metabolic properties of fructose. Absorbed fructose enters the liver but its metabolic fate differs considerably from glucose. Fructose bypasses the usual pathways that regulate glycolysis, resulting in increased availability of substrates for lipid synthesis.(12) In animal models and in early research in humans, substitution of sucrose with fructose resulted in increased postprandial triglyceride concentrations. In animal models, fructose has led to increased intrahepatic and intramuscular fat deposition (which are associated with insulin resistance).

Fructose ingestion does not directly stimulate insulin secretion, though it may stimulate insulin secretion indirectly by conversion of fructose to glucose via gluconeogenesis. Paradoxically, insulin in the central nervous system serves as a satiety signal, while it has an anabolic role in peripheral tissues; Havel(12) and others have speculated that the lower insulin response to fructose may reduce its ability to induce satiety. In addition, fructose is associated with reduced postprandial stimulation of the satiety hormone leptin and reduced suppression of the hunger hormone ghrelin.(12) Taken together, these factors provide compelling rationale for further investigation into the effects of fructose consumption on body weight, lipids and insulin.

The increase in fructose intake has raised concern about some specific metabolic properties of fructose.

It should be noted, however, that low to moderate intake of fructose (e.g. <60 g/d, the equivalent of about ten medium-sized pieces of most fruits) has not been shown to deleteriously influence lipid or glucose homeostasis. Indeed, for diabetics, small amounts of fructose may actually improve glycemia and reduce hepatic glucose output in response to insulin.(12)

A Sugar By Any Other Name Would Taste Just As Sweet?

Sugar alcohols and novel sugars have become increasingly popular in foods, as components in candy and chewing gum, and in cosmetic and other products. These sweeteners have been recently extensively reviewed(3) and are listed in Table 1.

Table 1. Non-Sugar Sweeteners.*

  Dietary Energy
(Kcal/gram)
FDA Status
Sugar Alcohols
Sorbitol 2.6 GRAS
Mannitol 1.6 Approved
Xylitol 2.4 Approved
Erythritol 0.2 GRAS
Novel Sugars
D-Tagtose 1.5 GRAS
Trehalose 4 GRAS
Nonnutritive Sweeteners
Aspartame 0 Approved
Acesulfame-K 0 Approved
Saccharin 0 Approved
Sucralose 0 Approved
Neotame 0 Approved

Adapted from (3).

Nutritive sweeteners include sugar alcohols and novel sugars. Sugar alcohols are derived from carbohydrates, most often from mono or disaccharides. Products containing sugar alcohols can be labeled as "sugar free" if they do not contain other sugars. Sugar alcohols are incompletely absorbed from the gastrointestinal tract and may be subject to fermentation in the colon to short chain fatty acids, which may be absorbed. The caloric value of each sugar alcohol varies with the degree of absorption as well as the degree of fermentation. Based on these properties, sugar alcohols, compared to sugars, reduce energy intake and blunt the glycemic response.

...Sugar alcohols, compared to sugars, reduce energy intake and blunt the glycemic response.

Sugar alcohols are also non-cariogenic and, although still controversial, may help retard dental caries. The etiology of dental caries is multifactorial and includes the effect of ingested food on saliva production, oral pH and oral microbiology. Ingested sugars may be fermented by oral bacteria to organic acids, leading to decreased pH of dental plaque. The decreased pH then promotes caries by increasing the solubility of dental enamel. Saliva itself has a relatively high pH and contains calcium and other minerals that promote mineralization of teeth. Ingestion of foods or other substances that increase saliva but do not contribute to production of organic acids (such as some sugar alcohols) may retard production of caries. Because of their incomplete absorption, many products containing sugar alcohols are required to warn of a laxative effect. Although sugar alcohol-containing products may decrease the absorbable energy content of foods, no long-term trials to assess a role in weight control were found.

Novel sugars include D-tagatose and trehalose. D-tagatose is an isomer of fructose, and only 20% is absorbed by the intestine and is subject to colonic fermentation. Trehalose is a disaccharide found in mushrooms. It is approximately half as sweet as sucrose and is absorbed completely. Trehalose is used as a sweetener, a food texturizer and a stabilizer.(3)

Nonnutritive Sweeteners

Nonnutritive sweeteners are among the most controversial of food additives. Table 1 above lists the five nonnutritive sweeteners approved in the U.S. as food additives.

Aspartame is the sweetener most surrounded by controversy. Aspartame is used in liquid, granular and powdered forms in over 6,000 products. It is approximately 200 times sweeter than sucrose and appears in the U.S. by the trade names NutraSweet, Equal and Sugar Twin. It decomposes when exposed to high heat and is inappropriate for baking.

Aspartame is a dipeptide methyl ester that is metabolized to phenylalanine, aspartatic acid and methanol. However, equal volumes of aspartame-sweetened beverages provide less phenynaline and aspartic acid than do equal volumes of beverages such as milk. Aspartame-sweetened beverages also provide less methanol than an equal volume of tomato juice.(3) Bolus doses of aspartame at the ADI of 50 mg/kg body weight/day (the equivalent of over 30 12-ounce cans of aspartame-sweetened soda) have not resulted in abnormal postprandial levels of the three metabolites in normal subjects or those who are heterozygous for phenylketonuria (PKU).(13)

Claims have been made that aspartame contributes to brain cancer, seizures, headaches, mood changes, cognitive alterations and allergic reactions. However, controlled studies in normal adults and children, those with heterozygous PKU, depression and attention deficit disorder have not demonstrated that acute or chronic intake of aspartame is associated with seizures, mood disturbances or impaired cognition.(13) In regard to brain cancer, case-control studies in children with brain cancer have demonstrated no link to maternal intake during pregnancy or lactation.(14) While idiopathic adverse reactions may certainly occur, there is no evidence to suggest that aspartame poses a general risk except to phenylketonurics, especially during pregnancy, or those with other errors of metabolism that could be adversely affected by metabolites.

In July 2005, the results of a study in rats were published revealing increased rates of lymphoma and leukemia in females.(15) Some critics of the study note that the cancer rates were observed over the entire lifespan of the animals (as opposed to shorter periods used in other studies) and questions regarding the historical controls used have arisen. At the very least, this study appears to have rekindled efforts to examine the toxicity of aspartame. Study results are currently being reviewed by the FDA and by European regulatory agencies, with opinions of these agencies expected in the next six months.

Saccharin was first synthesized in 1879 and remains in common use today. Saccharin appears in the U.S. by trade names Sweet'N Low, Sweet Twin, Sweet'N Low Brown and Necta Sweet. Originally considered GRAS, issues arose in 1977 concerning its carcinogenicity. Although never banned by the FDA, saccharin-containing products were required until 2001 to have a warning label that use had caused cancer in laboratory animals. However, it was subsequently concluded that the mechanism of saccharin-induced carcinogenicity in mice does not apply to humans and that saccharin does not pose increased cancer risk to humans.(14) No overall ADI has been issued, though specific recommendations for use as a tabletop sweeter (20 mg/teaspoon) or use in other products (12 mg/ounce of beverages) have been issued.

Sucralose is the disaccharide sucrose modified by substitution of chlorine for several hydroxyl groups. This modification makes it poorly absorbed and it is largely excreted unchanged in feces. When absorbed, it undergoes little metabolism and is largely excreted unchanged in the urine. It is approximately 600 times sweeter than sucrose, is heat stable and is used in variety of products. Sucralose appears in U.S. products with the trade name Splenda® and has an ADI of 5 mg/kg body weight/day.

Acesulfame potassium (or acesulfame-k) is approximately 200 times sweeter than sucrose, is heat stable and is used in a variety of foods worldwide where it is marketed by the name Sunett. It is often blended with other nonnutritive sweeteners. Acesulfame potassium is excreted largely unchanged and thus does not contribute substantial potassium to the diet. The ADI is 15 mg/kg body weight/day.

Neotame is derivative of a dipeptide methyl ester of phenylalanine and aspartic acid, which is metabolized to the de-esterified dipeptide and methanol, both of which are excreted in urine. Unlike aspartame, the individual amino acid constituents are not cleaved, thus neotame does not require a warning label for phenylketonurics. It is 7,000-13,000 times sweeter than sucrose, is available to be used as a tabletop sweetener and is present in a variety of foods including baked goods. Studies to-date have found no neurologic or other toxiciy. It has an ADI of 18 mg/kg body weight/day, although its intense sweetness suggests that far less would be needed for most sweetening purposes. However, there are some vocal critics who have expressed distrust, especially on Internet sites http://www.holisticmed.com/neotame/toxin.html), that research to-date documenting the safety of neotame is inadequate; such criticisms appear to focus most often on potential neurotoxicity and effects on the immune system due to the accumulation of amino acid and methanol metabolites such as formaldehyde.

Aspartame is the sweetener most surrounded by controversy.

Conclusions

The demand for sweet tasting food has increased and shows no sign of abating. There is little overall scientific evidence to suggest that intake of sugars should be dramatically reduced in our diets. However, common sense dictates that added sugars should not be consumed at the expense of diet quality or excess calories. The potential lipogenic and obesogenic qualities of fructose deserve further investigation but there appears to be little risk associated with fructose consumption that would be achieved by eating fruits and modest amounts of foods with added fructose as a sweetener. Nonnutritive sweeteners could theoretically replace caloric sweeteners and help stem increases in obesity but further research is needed to determine the role of nonnutritive sweeteners in weight loss, maintenance of weight loss or prevention of weight gain. Finally, despite considerable outcry in the public arena, toxicity of nonnutritive sweeteners has not been demonstrated.


Footnotes

1DuBois GE. Unraveling the biochemistry of sweet and umami tastes. Proc Natl Acad Sci U S A. 2004;101(39):13972-3.
2Drewnowski A, Kristal A, Cohen J. Genetic taste responses to 6-n-propylthiouracil among adults: a screening tool for epidemiological studies. Chem Senses. 2001;26(5):483-9.
3American Dietetic Association. Position of the American Dietetic Association: use of nutritive and nonnutritive sweeteners. J Am Diet Assoc. 2004;104(2):255-75.
4Popkin BM, Nielsen SJ. The sweetening of the world\'s diet. Obes Res. 2003;11(11):1325-32.
5Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet. 2001;357:505-508.
6Troiano RP, Briefel RR, Carroll MD, Bialostosky K. Energy and fat intakes of children and adolescents in the united states: data from the national health and nutrition examination surveys. Am J Clin Nutr. 2000;72(5 Suppl):1343S-1353S.
7Committee on Dietary Reference Intakes Food and Nutrition Board of the Institute of Medicine. (National Academies Press). Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. 2002.
8Blackburn GL, Kanders BS, Lavin PT, Keller SD, Whatley J. The effect of aspartame as part of a multidisciplinary weight-control program on short- and long-term control of body weight. Am J Clin Nutr. 1997;65(2):409-18.
9Kanders BS, Lavin PT, Kowalchuk MB, Greenberg I, Blackburn GL. An evaluation of the effect of aspartame on weight loss. Appetite. 1988;11 Suppl 1:73-84.
10Vermunt SH, Pasman WJ, Schaafsma G, Kardinaal AF. Effects of sugar intake on body weight: a review. Obes Rev. 2003;4(2):91-9.
11DiMeglio DP, Mattes RD. Liquid versus solid carbohydrate: effects on food intake and body weight. Int J Obes Relat Metab Disord. 2000;24(6):794-800.
12Havel PJ. Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev. 2005;63(5):133-57.
13European Commission Scientific Committee on Food. Opinion of the scientific committee on food; update on the safety of aspartame. 2002. europa.eu.int/comm/food/fs/sc/scf/out155_en.pdf, accessed 1/30/2006.
14Weihrauch MR, Diehl V. Artificial sweeteners--do they bear a carcinogenic risk? Ann Oncol. 2004;15(10):1460-5.
15Soffritti M et al. First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats. Environ Health Perspect doi:10.1289/ehp.8711 available via dx.doi.org [Online 10 November 2005].