Artificial Sweeteners: Agents of Insulin Resistance, Obesity and Disease

Artificial Sweeteners | The Paleo Diet

Introduction: Evolutionary Perspective

It’s pretty clear that if we follow the example of our hunter gatherer ancestors, artificial sweeteners should not be part of contemporary Stone Age diets. In my book, The Paleo Diet Revised (2010)1 I warned against drinking artificially sweetened soft drinks and further strengthened my opposition to all artificial sweeteners in 2012 with The Paleo Answer.2 Over the past few years numerous epidemiological (population), animal, tissue and human studies have demonstrated the adverse health effects of these synthetic chemicals. A particularly powerful study just published in the October 2014 issue of Nature3 provides a convincing argument against the use of artificial sweeteners in our food supply. If you consume artificial sweeteners in the form of sodas or foods once in a blue moon, they will have little or no adverse effects upon your long term health. However, I would never recommend that you drink artificially sweetened beverages or foods on a daily or even weekly basis, as they may promote insulin resistance,3, 4 obesity in adults5-7, 30-33 and children,8-11, 32, 44 metabolic syndrome diseases,12-18, 33 migraine headaches,19-23 adverse pregnancy outcomes,24-26 childhood allergies,24 and certain cancers.27-29

Artificial Sweeteners

The table* below shows the five artificial sweeteners that the U.S. Food and Drug Administration (FDA) has approved for consumption.

Artificial Sweeteners: Agents of Insulin Resistance, Obesity and Disease | The Paleo Diet

*Note that the artificial sweetener cyclamate was banned in the U.S. in 1969, but is still available in certain countries outside of the U.S.

In addition to these artificial sweeteners, the FDA has sanctioned a sugar substitute, stevia, as a dietary supplement since 1995. Stevia is a crystalline substance made from the leaves of a plant native to central and South America and is 100 to 300 times sweeter than table sugar. A concentrated derivative of stevia leaves called rebaudioside A was recently (2008) authorized by the FDA and goes by the trade names of Only Sweet, PureVia, Reb-A, Rebiana, SweetLeaf, and Truvia.

Since 1980 the number of people consuming artificially sweetened products in the U.S. has more than doubled.32, 33 Today, at least 46 million Americans regularly ingest foods sweetened by these chemicals – mainly in the form of soft drinks, or in a huge number of artificially sweetened products, including baby food.32, 33

Artificial Sweeteners and Obesity

If you were to ask most people why they drink artificially sweetened beverages, the resounding answer would be to enjoy a sweet drink without all the drawbacks of sugar laden sodas. Doesn’t everyone know that soft drinks sweetened with sugar promote obesity, type 2 diabetes and the Metabolic Syndrome (high blood pressure, high blood cholesterol and heart disease)? Of course, and the standard line of thought goes something like this, “if we remove refined sugars from our diets and replace them with artificial sweeteners, we would all be a lot healthier.” I can agree with the first and last parts of this argument, but not the second.

A number of large epidemiological studies5-7; 8-11, 44 and animal experiments34-43 indicate that artificially sweetened beverages may actually not be part of the solution to the U.S. obesity epidemic, but rather may be part of the problem.30-33 Unexpectedly, a series of large population based studies, including the San Antonio Heart Study6 examining 3,682 adults over a 7-8 year period; the American Cancer Society Study7 including 78,694 women; and the Nurses’ Health Study5 of 31,940 women have clearly demonstrated strong associations between increased intakes of artificial sweeteners and obesity. Alarmingly, these effects have been observed in children8, 11, 44 as well as in adults, and were utterly unanticipated because most artificial sweeteners were previously thought to be inert and not react with our gut or metabolism in an unsafe manner.30-33, 45

Laboratory Animal Experiments

In the course of the past few years, animal experiments have reversed these erroneous assumptions. Rats allowed to eat their normal chow consumed more food and gained more weight when artificial sweeteners were added to their diet.34-43 The best available evidence indicates that artificial sweeteners when consumed by either laboratory animals or humans promote weight gain by altering the normal gut bacterial biome3, 45 which in turn adversely affects glucose and insulin metabolism and consequently appetite. Who would have ever thought that a mass marketed product which supposedly was designed to help us lose weight may have actually caused exactly the opposite result? But wait, there is more.


In 1958 the federal government deemed both saccharin and cyclamate as “generally recognized as safe (GRAS)” artificial sweeteners. Eleven years later the FDA banned cyclamate and announced its intention to ban saccharin in 1977 because of worries over increased cancer risks from both of these chemicals. Consumer protests eventually led to a moratorium from congress on the ban for saccharin, but unfortunately it is still with us today. Aspartame was sanctioned for use as a sweetener by the FDA in 1996, followed by sucralose (1999), neotame (2002), and acesulfame (2003). You may think that anytime chemical additives such as artificial sweeteners were permitted into our food supply, they would have been thoroughly tested and conclusively shown to be safe. Unfortunately, this is not always the case, and the potential toxicity of some of these sweetening compounds are widely disputed in the scientific community, particularly in light of newer, more carefully controlled animal studies.27-29

A series of more recent experiments29 from Dr. Soffritti’s laboratory in Bologna, Italy have shown that even low doses of aspartame given to rats over the course of their lives leads to increased cancer rates. This study is important, because many people may consume much higher concentrations of this chemical by drinking artificially sweetened beverages on a daily basis for years and years.


Aspartame has also been shown to trigger migraine headaches in certain people because it breaks down into a compound called methanol (otherwise known as wood alcohol) in our bodies. And it’s not just aspartame that may prove dangerous to our health when we ingest these synthetic concoctions on a regular basis. Recent animal experiments27 have revealed that saccharin, acesulfame as well as aspartame caused DNA damage in mice bone marrow. Frequently, it is difficult to translate results from animal experiments into, meaningful recommendations for humans, because large epidemiological studies generally don’t show artificial sweeteners to be risk factors for cancer. Does this mean that these compounds are completely safe? Absolutely not.


A 2010 prospective study25 of 59,334 pregnant women from Denmark showed for the first time that consumption of artificially sweetened soft drinks significantly increased the risk for pre-term delivery (less than 37 weeks). This condition shouldn’t be taken lightly, as it represents the leading cause of infant death. An interesting outcome of this study was that only artificially sweetened beverages increased the risk for pre-term delivery – and not sugar sweetened soft drinks. A follow-up study confirmed these results.26 Am I recommending that pregnant women consume sugary soft drinks? Emphatically no! But these studies indicate that sugar sweetened drinks may be less harmful to your developing fetus than are artificially sweetened soft drinks.


Loren Cordain, Ph.D., Professor Emeritus


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2. Cordain L. The Paleo Answer. John Wiley & Sons, NY New York, 2012

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11. Brown RJ, de Banate MA, Rother KI. Artificial sweeteners: a systematic review of metabolic effects in youth. Int J Pediatr Obes. 2010 Aug;5(4):305-12

12. Nettleton JA, Lutsey PL, Wang Y, Lima JA, Michos ED, Jacobs DR Jr. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2009 Apr;32(4):688-94.

13. Cohen L, Curhan G, Forman J. Association of sweetened beverage intake with incident hypertension. J Gen Intern Med. 2012 Sep;27(9):1127-34.

14. Gardener H, Rundek T, Markert M, Wright CB, Elkind MS, Sacco RL. Diet soft drink consumption is associated with an increased risk of vascular events in the Northern Manhattan Study. J Gen Intern Med. 2012 Sep;27(9):1120-6.

15. Dhingra R, Sullivan L, Jacques PF, Wang TJ, Fox CS, Meigs JB, D’Agostino RB, Gaziano JM, Vasan RS.Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation. 2007 Jul 31;116(5):480-8.

16. Lutsey PL, Steffen LM, Stevens J. Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities study. Circulation. 2008 Feb 12;117(6):754-61

17. Fagherazzi G, Vilier A, Saes Sartorelli D, Lajous M, Balkau B, Clavel-Chapelon F.
Consumption of artificially and sugar-sweetened beverages and incident type 2 diabetes in the Etude Epidemiologique aupres des femmes de la Mutuelle Generale de l’Education Nationale-European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 2013 Mar;97(3):517-23

18. Greenwood DC, Threapleton DE, Evans CE, Cleghorn CL, Nykjaer C, Woodhead C, Burley VJ. Association between sugar-sweetened and artificially sweetened soft drinks and type 2 diabetes: systematic review and dose-response meta-analysis of prospective studies. Br J Nutr. 2014 Sep 14;112(5):725-34.

19. Abegaz EG, Bursey RG. Formaldehyde, aspartame, migraines: a possible connection. Dermatitis. 2009 May-Jun;20(3):176-7; author reply 177-9

20. Bigal ME, Krymchantowski AV. Migraine triggered by sucralose–a case report. Headache. 2006 Mar;46(3):515-7

21. Jacob SE, Stechschulte S. Formaldehyde, aspartame, and migraines: a possible connection. Dermatitis. 2008 May-Jun;19(3):E10-1.

22. Lipton RB, Newman LC, Cohen JS, Solomon S. Aspartame as a dietary trigger of headache. Headache. 1989 Feb;29(2):90-2

23. Newman LC, Lipton RB. Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches. Headache. 2001 Oct;41(9):899-901.
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24. Maslova E, Strøm M, Olsen SF, Halldorsson TI. Consumption of artificially-sweetened soft drinks in pregnancy and risk of child asthma and allergic rhinitis.PLoS One. 2013;8(2):e57261.

25. Halldorsson TI, Strøm M, Petersen SB, Olsen SF. Intake of artificially sweetened soft drinks and risk of preterm delivery: a prospective cohort study in 59,334 Danish pregnant women. Am J Clin Nutr. 2010 Sep;92(3):626-33.

26. Englund-Ögge L1, Brantsæter AL, Haugen M, Sengpiel V, Khatibi A, Myhre R, Myking S, Meltzer HM, Kacerovsky M, Nilsen RM, Jacobsson B. Association between intake of artificially sweetened and sugar-sweetened beverages and preterm delivery: a large prospective cohort study. Am J Clin Nutr. 2012 Sep;96(3):552-9.

27. Bandyopadhyay A, Ghoshal S, Mukherjee A. Genotoxicity testing of low-calorie sweeteners: aspartame, acesulfame-K, and saccharin. Drug Chem Toxicol. 2008;31(4):447-57

28. Belpoggi F, Soffritti M, Padovani M, Degli Esposti D, Lauriola M, Minardi F. Results of long-term carcinogenicity bioassay on Sprague-Dawley rats exposed to aspartame administered in feed. Ann N Y Acad Sci. 2006 Sep;1076:559-77.

29. Soffritti M, Belpoggi F, Tibaldi E, Esposti DD, Lauriola M. Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats. Environ Health Perspect. 2007 Sep;115(9):1293-7

30. Ferreira AV1, Generoso SV, Teixeira AL. Do low-calorie drinks ‘cheat’ the enteral-brain axis? Curr Opin Clin Nutr Metab Care. 2014 Sep;17(5):465-70.

31. Swithers SE, Martin AA, Davidson TL. High-intensity sweeteners and energy balance. Physiol Behav. 2010 Apr 26;100(1):55-62

32. Yang Q. Gain weight by “going diet?” Artificial sweeteners and the neurobiology of sugar cravings: Neuroscience 2010. Yale J Biol Med. 2010 Jun;83(2):101-8.

33. Swithers SE. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends Endocrinol Metab. 2013 Sep;24(9):431-41.

34. Swithers SE, Davidson TL. A role for sweet taste: calorie predictive relations in energy regulation by rats. Behav Neurosci. 2008 Feb;122(1):161-73.

35. Swithers SE, Baker CR, Davidson TL. General and persistent effects of high-intensity sweeteners on body weight gain and caloric compensation in rats. Behav Neurosci. 2009 Aug;123(4):772-80

36. Swithers SE, Martin AA, Clark KM, Laboy AF, Davidson TL. Body weight gain in rats consuming sweetened liquids. Effects of caffeine and diet composition. Appetite. 2010 Dec;55(3):528-33

37. Feijó Fde M1, Ballard CR, Foletto KC, Batista BA, Neves AM, Ribeiro MF, Bertoluci MC. Saccharin and aspartame, compared with sucrose, induce greater weight gain in adult Wistar rats, at similar total caloric intake levels. Appetite. 2013 Jan;60(1):203-7.

38. Swithers SE, Sample CH, Davidson TL. Adverse effects of high-intensity sweeteners on energy intake and weight control in male and obesity-prone female rats. Behav Neurosci. 2013 Apr;127(2):262-74.

39. Pierce WD, Heth CD, Owczarczyk JC, Russell JC, Proctor SD. Overeating by young obesity-prone and lean rats caused by tastes associated with low energy foods. Obesity (Silver Spring). 2007 Aug;15(8):1969-79.

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41. Polyák E, Gombos K, Hajnal B, Bonyár-Müller K, Szabó S, Gubicskó-Kisbenedek A, Marton K, Ember I. Effects of artificial sweeteners on body weight, food and drink intake. Acta Physiol Hung. 2010 Dec;97(4):401-7

42. Malaisse WJ, Vanonderbergen A, Louchami K, Jijakli H, Malaisse-Lagae F. Effects of artificial sweeteners on insulin release and cationic fluxes in rat pancreatic islets. Cell Signal. 1998 Nov;10(10):727-33

43. Swithers SE, Laboy AF, Clark K, Cooper S, Davidson TL. Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats. Behav Brain Res. 2012 Jul 15;233(1):1-14

44. Berkey CS, Rockett HR, Field AE, Gillman MW, Colditz GA. Sugar-added beverages and adolescent weight change. Obes Res. 2004 May;12(5):778-88.

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About Loren Cordain, PhD, Professor Emeritus

Loren Cordain, PhD, Professor EmeritusDr. Loren Cordain is Professor Emeritus of the Department of Health and Exercise Science at Colorado State University in Fort Collins, Colorado. His research emphasis over the past 20 years has focused upon the evolutionary and anthropological basis for diet, health and well being in modern humans. Dr. Cordain’s scientific publications have examined the nutritional characteristics of worldwide hunter-gatherer diets as well as the nutrient composition of wild plant and animal foods consumed by foraging humans. He is the world’s leading expert on Paleolithic diets and has lectured extensively on the Paleolithic nutrition worldwide. Dr. Cordain is the author of six popular bestselling books including The Real Paleo Diet Cookbook, The Paleo Diet, The Paleo Answer, and The Paleo Diet Cookbook, summarizing his research findings.

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“7” Comments

  1. None of the studies mentioned are conclusive. There is no body of evidence to support that artificial sweetener (aspartame in particular, as the most controversial) cause weight gain or adverse health effects. Sugar, on the other hand, has plenty of studies which evidence their harm to human health.

  2. I read the article and interpreted that Stevia is an artificial sweetener for all intents and purposes as far as biochemistry and effect regarding obesity goes. My friends who I share this article with though get hung up on the classification as a natural sugar substitute and dietary supplement, indicating that it is not artificial, it is not an artificial sweetener and is not included for any of the negative aspects according to the above article. I understand not wanting to beat a dead horse, but the confusing legal and regulatory language our government uses to classify substances transcends the confusion through your article to the audience. I would like to believe that I understand your intent and my friends are misinterpreting, but I cannot be sure.

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  7. Lets not forget the . . . tol sweeteners. For example, maltitol is heavily used in sugar free chocolate. Sorbitol is another well known “alcohol sugar.” In my case both of these cause the lining of my large intestine to freeze up and expand. It locks up the entire digestive system for me – very painful. I won’t tell you the whole story but these so-called sugar substitutes are used heavily in baking and candy. Got IBS? Try staying away from these and see what happens!

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  15. Stevia is a natural growing plant.
    I do worry about how the leaf is processed but
    as far as I know, it is not chemically altered (cis-trans bonds or adding molecules).

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