By Amber M. Healy, DO
Assistant Professor of Diabetology, Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Diabetes Fellow, O’Bleness Health System, Athens, Ohio
Dr. Healy reports no financial relationships relevant to this field of study.
Americans are addicted to sugar. The U.S. Department of Agriculture estimates consumption of sugars and sweeteners to be 150 pounds per year per person. There are more processed food and beverage choices than ever, and many of them contain processed sweeteners such as high fructose corn syrup or artificial sweeteners. In addition, rates of obesity and type 2 diabetes are at epidemic levels in the United States. The concern is that consumption of these fake sugars may be to blame for weight gain and increased rates of type 2 diabetes. There are convincing mechanisms to support this as a feasible hypothesis, but the evidence is inconclusive based on the research studies completed to date.
In 2003-2004, Americans consumed an estimated 585 grams (20.6 ounces) of beverages with added sugar and 381 grams (13.4 ounces) of food with added sugar per day.1 At the same time, sugar substitutes have become a staple in the American diet. Artificial sweeteners have been around since the 1800s, with saccharin being the first synthesized in 1879.2 High-fructose corn syrup (HFCS) was discovered in 1957, and in recent years it has become a cheaper substitute for sugar in a variety of beverages and food products. Artificial sweeteners were developed to provide sugar-free alternatives for those needing less sugar in their diets or those trying to lose weight; use has risen over the last 30 years.1 However, many questions linger. What are the risks of these manmade substances used in place of sugar? Is it a coincidence that there is more obesity and diabetes as these products have gained popularity? Is moderation the key and has consumption of these substances become excessive? This article will try to answer some of these questions and provide guidance for talking to patients about artificial sweeteners.
High-fructose Corn Syrup
HFCS represents 40% of sweeteners added to food in the United States.3 In 1957, Marshall and Kooi published a paper about the synthesis of fructose from glucose.4 Their process was not conducive to mass production so it was not adopted at that time. Between 1965-1970, a Japanese scientist developed a way to commercially manufacture fructose. In the United States between 1975 and 1985, sucrose use in processed foods and soft drinks started, because the cost of importing sugar (also known as sucrose) became more expensive. HFCS became a cheaper, sweeter, sweetening alternative, as well as a way for the United States to make use of an overproduction of corn. The U.S. government saw this as an opportunity to subsidize its use.
Fructose does not require insulin to enter the cells. It is primarily taken up by the liver to become glucose, glycogen, and acetyl CoA, which becomes triglycerides. HFCS is a fructose made from corn starch. The corn starch becomes a syrup that is mixed with enzymes to change glucose to fructose. By chromatography HFCS is 42% fructose, but commercially used HCFS is 55% fructose so its sweetness is equivalent to sugar in taste and sweetness. This preparation also has fewer calories than sugar.5 The syrup is a mixture of HFCS 55, which is 55% fructose, 40% glucose, and 5% higher saccharide. Crystalline fructose and HFCS, which are two different forms of fructose, have similar effects on blood glucose levels, but HFCS causes more dramatic increases in blood glucose as compared to crystalline fructose.6
Some argue that there is no difference between fructose and HFCS. Fructose is a naturally occurring monosaccharide found in fruit. So what is the difference between fructose and HFCS? HFCS is consumed in higher concentrations and in liquid, so it is absorbed more readily into the bloodstream, whereas the fructose in a piece of fruit is mixed with fiber at a lower concentration, thus leading to a slower absorption. Another point to consider is that HFCS has been engineered to have a higher concentration of fructose than the concentration of fructose in sucrose when the same amount of sweetener is used in food.5 The higher fructose load from HFCS may lead to high triglycerides with recurrent exposure as explained below. The connection between HFCS and pancreatic insulin secretion or insulin resistance is complicated, though the consumption of HFCS has not itself been directly linked to the development of diabetes.
Fructose enters the glycolytic pathway through fructose-1-phosphate, which bypasses the rate-controlling step of glycolysis (see Figure 1). This leads to unregulated amounts of lipogenic substrates and increased triglycerides.7 Postprandial hypertriglyceridemia is promoted by fructose-containing foods. This has been shown to occur within 24 hours of fructose consumption, but effects on de novo lipogenesis and whether triglyceride levels remain high with prolonged consumption of HFCS are not known.3 The effect of fructose vs a high glucose diet was studied, and by day 42 of the trial elevated low density lipoprotein cholesterol (LDL) disappeared in subjects receiving fructose.5 In this same study, fasting triglycerides were elevated in males but not in females in the fructose group.5 Another study comparing groups consuming fructose, sucrose (half glucose and half fructose), and glucose found that LDL cholesterol was elevated in the fructose and sucrose groups but not in the glucose group.8 Postprandial triacylglycerol levels were comparable in HFCS, sucrose, and 100% fructose, all of which are fructose-containing substances.7
Fructose can cause weight gain because it does not stimulate insulin secretion or leptin production in the adipose tissue. Stanhope and Havel demonstrated that fructose-sweetened beverage consumption led to lowered circulating concentrations of leptin, insulin, and glucose. The decreased circulating leptin levels led to less postprandial suppression of ghrelin.7,9 Ghrelin is orexigenic, which means that it promotes appetite. Secretion of ghrelin occurs in a pulsatile manner, where it is highest before eating and then decreases with food intake.10 Insulin, leptin, and ghrelin signal to the central nervous system to provide signals of satiety. This means that the effects of fructose on ghrelin through the suppression of leptin can lead to a lack of satiety and increased caloric intake. Increased caloric intake can lead to weight gain and obesity (see Figure 2).
The relationship between the development of diabetes and fructose or high fructose consumption is not well established. One study showed that hepatic insulin sensitivity decreased with small amounts of daily fructose consumption.8 This may indicate that there is a relationship to insulin resistance and fructose that could potentially lead to the development of type 2 diabetes. It is well known that weight gain and insulin resistance are risk factors for the development of diabetes. So it appears that between the effects of fructose on ghrelin and its influence on weight gain and the effects of fructose on insulin resistance that fructose may contribute to the development of type 2 diabetes.
Artificial Sweeteners
Figure 1: Glycolytic Pathway Leading Triacylglycerol
The flow chart provides a simplified review of glycolytic pathway leading triacylglycerol, which is the precursor for triglycerides. The hexokinase enzyme is the rate-limiting step of glycolysis that is not required for fructose to enter the glycolytic pathway.
Americans are eating more sugar than ever, especially added sugar in sweetened beverages. A way to decrease this consumption has been to consume non-nutritive sweetened beverages. There are multiple different formulations of artificial sweeteners with new ones being approved in recent years. Aspartame was the first to be approved by the FDA in 1981. Other approved non-nutritive sweeteners include saccharin, sucralose, acesulfame K, and neotame. Each of these artificial sweeteners is much sweeter than table sugar (see Table).
| Table: Sweetness Comparison Between Artificial Sweeteners and Sucrose | |
|---|---|
| Artificial sweeteners | Sweentness relative to sucrose |
| Acesulfame K | 200 |
| Aspartame | 180 |
| Neotame | 8000 |
| Saccharin | 300-500 |
| Sucralose | 600 |
| HFCS | ~1 |
| Glucose | 0.5-1 |
| Fructose | 1-2 |
| Honey | 1 |
| Stevia | 300 |
One thing that most artificial sweeteners have in common is that they were accidental discoveries, later being approved by the FDA. Saccharin was discovered in 1879 when Constantin Fahlberg was analyzing components of coal tar. He went to dinner one night and picked up a roll to find that it was very sweet. Earlier in the day he had spilled his experiment on his hands. He went back to the lab to find the substance.11 In 1965, James Schlatter was recrystalizing aspartame in ethanol and licked his fingers to turn a page, discovering that aspartame was sweet.12 In 1967, acesulfame K was also discovered by the licking of fingers after touching the substance.12 Sucralose was discovered in 1976 when two scientists were asked to test a chlorinated sugar but misunderstood and thought that they were supposed to taste it instead of test it.13
Figure 2: Hormone Effects on Hypothalamus that Affect Satiety
Figure 3: Glucagon-like Peptide-1 Effects on the Body that Lead to Decreased Glucose Levels and Decreased Caloric Consumption
In general, many people believe consuming non-caloric or non-nutritive sweeteners promotes weight loss. But is this really the case? The consensus appears to be that non-caloric sweeteners do not lead to weight loss nor do they prevent weight gain.1,14 Non-caloric sweeteners do not seem to promote the same satiety as caloric sweeteners. Artificial sweeteners have been shown to affect glucagon like peptide-1 (GLP-1) secretion. GLP-1 secretion from the L cells in the intestine is dependent on the presence of carbohydrates, lipids, and proteins. It slows stomach emptying, promoting satiety (see Figure 3). One study in adolescents and young adults tested the effects of 75 gram glucose loads after drinking a diet soda or unflavored carbonated water.15 Three hours after the glucose load the glucose, GLP-1, and insulin were measured; the insulin levels between the two groups were not that different and the GLP-1 was elevated in the diet soda group.15 Different studies have been done to look at GLP-1 with different sweeteners. Sucralose has been shown to elicit a GLP-1 response whereas aspartame has not.1 Another study looking at individuals with a body mass index (BMI) of 42 demonstrated that when given sucralose prior to an oral glucose tolerance test, blood sugars peaked at higher levels and insulin levels were 20% higher compared to receiving water prior to an oral glucose tolerance test.16 This suggests that artificial sweeteners affect blood sugar level and insulin secretion. The mechanism behind this is not known. The influence of artificial sweeteners on appetite, energy balance, and body weight have not been fully characterized.
Another study examined 224 adolescents over a 2-year period. Both groups had their BMIs measured at the beginning of the study. The experimental group was provided with noncaloric beverages every 2 weeks and three phone calls were made to parents as motivation. The control group did not get this attention.17 At the end of 2 years, there was no difference in the two groups with respect to BMI.17 One might conclude that artificially sweetened beverages do not help with weight loss, but we could also say that they do not cause weight gain. Another study compared the effects of ad libitum food intake in a group consuming sucrose-sweetened beverages to a group consuming artificially sweetened beverages over a 10-week period.18 Results showed that those consuming sucrose-sweetened beverages had a 28% increase in calorie intake in the form of carbohydrates and a decrease in protein and fat intake. They also gained weight and increased their fat mass.18 The MESA study followed patients for 3 years to look for the development of type 2 diabetes and metabolic syndrome. The incidence of diabetes was assessed in three follow-up exams where participants self-reported type 2 diabetes diagnosis based on blood sugar, self-reported diagnosis, or the use of diabetes medications.19 Participants were asked about consumption of diet soda and regular soda; 14% of participants consumed at least one diet soda daily. Follow-up of the participants revealed a 67% higher rate of type 2 diabetes in those who consumed diet soda compared to those who did not consume diet soda.19 This association was reported to be independent of baseline measurements.19 Another study looked at men and their risk of type 2 diabetes, and an association of sugar-sweetened and artificially sweetened beverages.20 Results showed that sugar-sweetened beverages were associated more with the diagnosis of type 2 diabetes.20 The results of this study, however, are not unexpected. Some of the sugar-sweetened beverages in this study contained HFCS. The artificially sweetened beverage consumption in the San Antonio Heart Study cohort was analyzed and a dose response effect was found.21 Those individuals who consumed more artificially sweetened beverages gained more weight.21 Individuals of normal weight who consumed more than 21 artificially sweetened beverages a week doubled their risk of becoming obese. The change in BMI in those individuals who consumed artificially sweetened beverages increased by 47% compared to those who did not consume artificially sweetened beverages.21 Other risk factors such as gender, ethnicity, diet, diabetes, and exercise were considered and consistently showed higher weight gain in the individuals consuming more artificially sweetened beverages.21
These studies have shown a spectrum of possible effects of artificial sweeteners. They affect appetite by decreasing satiety. Although artificial sweeteners did not affect weight in teens or adults, there was an increased incidence of type 2 diabetes demonstrated in a consumption survey. One study showed that increased consumption of artificially sweetened beverages led to increased BMI. Another study did not show this same result in men; however, the food frequency questionnaire also showed that those who consumed the sugar-sweetened beverages also had poorer diets compared to those who consumed artificially sweetened beverages.20
Discussion
Sugar is an unhealthy addiction in the United States and is increasing worldwide. Consumption of HFCS peaked in 1998 at 54 gallons per person, but by 2011 it had decreased to 21 gallons.16 A Bloomberg Report found a decreased fondness for corn sugar and soft drinks in general, and cited that more people are choosing to drink water, juice, and tea.16 Although it is a promising sign that the nation is becoming more health conscious, there has been an increasing popularity of artificial sweeteners. The thought behind artificial sweeteners is that the feeling of deprivation from sugar will be less without increasing blood glucose levels or leading to weight gain. However, there is evidence that artificial sweeteners are not necessarily the healthy alternatives that they were once thought to be. A position paper by Gardner et al concluded that there is not enough evidence to confirm that artificial sweeteners should be recommended to replace caloric sweeteners, but that the better approach is to decrease the amount of added sugar in one’s diet. 22
Novel sweeteners, such as stevia, tagalose, and trehalose, will be another category to observe as more research is done. Stevia is extracted from Stevia rebuadiana, a perennial shrub species. Extracts from this plant have been used for the treatment of diabetes in South America. One study demonstrated that the polyphenol component extracted from the plant was beneficial in treating hyperglycemia, improving glomerular filtration rate, and improving hepatic injury in rats with diabetes.23 Stevia may be a safer option as a sweetener; however, more studies will need to be done. The commercially available brand Truvia® is a blend of erythritol and stevia. Tagalose and trehalose are also naturally occurring substances that are not as well researched.
Another type of sweetener is erythritol, which is a sugar alcohol. Other sugar alcohols include mannitol, xylitol, and sorbitol. Sugar alcohols are added to many "sugar-free" items like candy, gum, and other sweets and are meant to enhance the sweetness of the artificial sweetener. Blood sugar is affected by sugar alcohols and, when consumed in large quantities, can cause diarrhea and bloating.
How do we counsel our patients who are confused about food labels and believe that reduced sugar or no added sugar automatically means a better choice? Discuss the facts: "Sugar-free" or "no sugar added" do not mean that a food product does not contain sugar. Many products contain sugar alcohols that will raise blood sugar. More natural alternatives — including honey, maple syrup, agave nectar, and fruit juice — may be better choices. Some argue that these substances also contain fructose, but smaller amounts of naturally occurring fructose are likely to be better choices than HFCS. These natural choices may also raise blood sugar, so moderation is important. Detrimental health effects also can occur with the overconsumption of these more natural sweetening agents. When it comes to beverages, water and unsweetened tea are best, and, if some sweetness is desired, seltzer water with some real fruit juice could provide an alternative. Providing patients with education about the various sweeteners and substances containing sugar, sugar alcohols, and HFCS and encouraging moderation is beneficial to their overall health given the lack of a strong conclusion about the consumption of these products in general.
Summary Points
- Artificial sweeteners have been engineered to be hundreds to thousands times sweeter than table sugar, which allows small amounts to be used in food and drinks and allows them to be low calorie and sugar-free.
- High fructose corn syrup alters the effects of leptin and ghrelin, which decrease satiety and lead to increased food intake that can cause weight gain.
- Studies suggest that sugar-sweetened beverages and artificial sweeteners both can contribute to the development of type 2 diabetes, but more studies are needed to confirm that there is a more direct relationship.
References
- Mattes R, Popkin B. Nonnutritive sweetner consumption in humans: Effects on appetite and food intake and their putative mechanisms. Am J Clin Nutr 2009;89:1-14.
- Tandel K. Sugar substitutes: Health controversy over perceived benefits. J Pharmacol Pharmacother 2011;2:236-243.
- Stanhope K, et al. Twenty-four hour endocrine and metabolic profile following consumption of high fructose corn syrup, sucrose-fructose, and glucose-sweetened beverage with meals. Am J Clin Nutr 2011;94:112-119.
- Marshall R, Kooi E. Enzymatic conversion from D-glucose to D-fructose. Science 1957;125:648-649.
- Bantle J. Do fructose and sugar alcohols make a difference in diabetes management and weight control? ADA Conference-San Francisco. 2006;Webcast.
- Argun S, Ertel N. Plasma glucose and insulin after fructose and high fructose corn syrup meals in subjects with non-insulin-dependent diabetes mellitus. Diabetes Care 1981;4:464-467.
- Stanhope KL, Havel PJ. Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high fructose corn syrup. Am J Clin Nutr 2008;88:1733S-1737S.
- Aebereli I, et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: A randomized controlled trial. Diabetes Care 2013;36:150-156.
- Teff K, et al. Dietary fructose reduces circulatory insulin, leptin, atenuates postprandial suppression of ghrelin and increases triglycerides in women. J Clin Endocrinol Metab 2004;89:2963-2972.
- Higgins SC, et al. Ghrelin: The peripheral hunger hormone. Ann Med 2007;39:116-136.
- Hicks J. The pursuit of sweet: A history of saccharin. Available at: www.chemheritage.org. Accessed May 17, 2013.
- Hodgin G. The history, synthesis, metabolism and uses of artificial sweeteners. Available at: http://monsanto.unveiled.info/products/aspartme.htm. Accessed May 17, 2013.
- Sweeteners. Virtual Chembook Elmhurst College Web site. Available at: www.elmhurst.edu/~chm/vchembook/549sweet.html. Accessed June 30, 2013.
- Wiebe N, et al. A systematic review on the effect of sweeteners on glycemic responses and clinically relevant outcomes. BMC Med 2011;9:123.
- Brown R, et al. Ingestion of diet soda before glucose load augments glucagon-like peptide-1 secretion. Diabetes Care 2009;32:2184-2186.
- Bjerga A. U.S. losing a taste for corn sweetener as dieters shun soda. Bloomberg Jan. 22, 2013. Available at: http://www.bloomberg.com/news/2013-01-22/u-s-losing-taste-for-corn-sweetener-as-dieters-shun-soda.html. Accessed June 30, 2013.
- Ebbeling CB, et al. A randomized trial of sugar-sweetened beverage and adolescent body weight. N Engl J Med 2012;367:1407-1416.
- Raben A, et al. Sucrose compared with artificial sweeteners: Different effects on ad libitum food intake and body weight after 10 weeks of supplementation in overweight subjects 1,2,3. Am J Clin Nutr 2002;76:721-729.
- Nettleton J, Lutsey P. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in multi-ethnic study of athrosclerosis (MESA). Diabetes Care 2009;32:688-693.
- de Koenig L, et al. Sugar-sweetened and artificially sweetened beverage consumption and risk of type 2 diabetes in men. Am J Clin Nutr 2011;93:1321-1327.
- Fowler S, et al. Fueling the obesity epidemic? Artificially sweetened beverage use and long term weight gain. Obesity 2008;16:1894-1900.
- Gardner C, et al. Nonnutritive sweeteners: Current use and health perspectives. Diabetes Care 2012;35:1798-1808.
- Shivanna N, et al. Antioxidant, anti-diabetic, and renal protective properties of Stevia rebaudiana. J Diabetes Complications 2013;27:103-113.
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