February 1, 2006

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.

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; people have been enslaved over sugar; and sugar has played large roles in national economies. You are born with a preference for sweet taste. The degree to which we prefer a sweet taste appears to vary because of factors such as genetic differences in taste receptors, age and exposure to sweet foods.

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 very little 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).

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.

Measuring Consumption
Consumption of sweeteners is most often measured 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.

High fructose corn syrup was introduced commercially in the 1960s and most of it is the product of enzymatic conversion of cornstarch to glucose and fructose, in proportions of 42%, 55% or 90% fructose.

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 most of it 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%, and sweeteners from soft drinks and fruit drinks accounted for almost one-third of total daily sweetener intake. 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.
Sweetener Consumption chart
Source: USDA.

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. In some surveys, consumption of sweetened soft drinks such as soda has been associated with overweight and gains of weight.However, other surveys have found no relationship between sweeteners and energy intake, body weight or obesity.

Sweetened beverages, such as soda or fruit drinks, may be of particular concern because...[r]esearch suggests that...we do not adjust our intake of other foods to compensate for the liquid calories.

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. 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. Based on these limited studies, it appears that replacement of nutritive sweeteners with nonnutritive sweeteners or complex carbohydrates does not help you lose weight. 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. 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, lipid disorders, obesity, dental caries and behavioral problems. 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.

Fructose: Especially Harmful?
The increased intake of high fructose corn syrup has raised concern because the absorbed fructose enters the liver but is not broken down by the usual pathways that handle simple sugar (glucose). As a consequence, less insulin, the hormone which regulates blood sugar levels, is released and extra products that can be used to make fats are produced and released into the bloodstream. Since insulin secretion helps regulate appetite by stimulating the release of the hormone leptin, which tells the brain you have eaten enough and, at the same time, suppresses the hunger hormone, ghrelin. fructose may thus make you eat more and gain weight.

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 produce extra blood fats or interfere with blood sugar levels. Indeed, for diabetics, small amounts of fructose may actually improve blood sugar control.

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 and are listed in Table 1.

Table 1.
Non-Sugar Sweeteners.*
Dietary Energy
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 .

Nutritive sweeteners include sugar alcohols and novel sugars. Sugar alcohols are derived from carbohydrates. 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. Compared to sugars, sugar alcohols reduce energy intake and don't produce sharp rises in blood sugar. Sugar alcohols are also non-cariogenic and, although still controversial, may help retard dental caries. Because of their incomplete absorption, many products containing sugar alcohols are required to warn of a laxative effect.

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.

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. 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, after eating, in abnormal levels of the three metabolites in normal subjects or those who are heterozygous for phenylketonuria (PKU).

Claims have been made that aspartame contributes to brain cancer, seizures, headaches, mood changes, cognitive alterations and allergic reactions. Giving subjects a one-time large dose of aspartame at the ADI of 50 mg/kg body weight/day (the equivalent of over 30 12-ounce cans of aspartame-sweetened soda) has not resulted in abnormal levels of break down products in normal subjects or even in those who are carriers for the metabolic disorder phenylketonuria (PKU). Controlled studies in normal adults and children, PKU carriers, those who suffer from depression or attention deficit disorder have similarly not demonstrated that acute or chronic intake of aspartame is associated with seizures, mood disturbances or impaired cognition. In regard to brain cancer, case-control studies in children with brain cancer have demonstrated no link to maternal intake during pregnancy or lactation.

In July 2005, the results of a study in rats were published revealing increased rates of the cancers lymphoma and leukemia in females. 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. 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 that has been modified chemically. The 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 similar to aspartame but because of its chemical structure does not, unlike aspartame, require a warning label for individuals with phenylketonuria. 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 (, 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 metabolites such as formaldehyde.

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 fat-creating and weight-gaining 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.

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