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Understanding the metabolic and health effects of low-calorie sweeteners: methodological considerations and implications for future research

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Abstract

Consumption of foods, beverages, and packets containing low-calorie sweeteners (LCS) has increased markedly across gender, age, race/ethnicity, weight status, and socio-economic subgroups. However, well-controlled intervention studies rigorously evaluating the health effects of LCS in humans are limited. One of the key questions is whether LCS are indeed a beneficial strategy for weight management and prevention of obesity. The current review discusses several methodological considerations in the design and interpretation of these studies. Specifically, we focus on the selection of study participants, inclusion of an appropriate control, importance of considering habitual LCS exposure, selection of specific LCS, dose and route of LCS administration, choice of study outcomes, and the context and generalizability of the study findings. These critical considerations will guide the design of future studies and thus assist in understanding the health effects of LCS.

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References

  1. Esterl M: The Diet Soda Business Is in Freefall. In The Wall Street Journal 2014. http://www.wsj.com/articles/SB10001424052702304157204579473772336022200. Accessed 2 Oct 2016.

  2. Sylvetsky AC, Welsh JA, Brown RJ, Vos MB. Low-calorie sweetener consumption is increasing in the United States. Am J Clin Nutr. 2012;96:640–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Drewnowski A, Rehm CD: Socio-demographic correlates and trends in low-calorie sweetener use among adults in the United States from. to 2008. Eur J Clin Nutr. 1999;2015(69):1035–41.

    Google Scholar 

  4. Malik VS, Pan A, Willett WC, Hu FB. Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98:1084–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scheurer M, Brauch HJ, Lange FT. Analysis and occurrence of seven artificial sweeteners in German waste water and surface water and in soil aquifer treatment (SAT). Anal Bioanal Chem. 2009;394:1585–94.

    Article  CAS  PubMed  Google Scholar 

  6. Arbelaez P, Borrull F, Pocurull E, Marce RM. Determination of high-intensity sweeteners in river water and wastewater by solid-phase extraction and liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2015;1393:106–14.

    Article  CAS  PubMed  Google Scholar 

  7. Swithers SE. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends Endocrinol Metab. 2013;24:431–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sylvetsky A, Rother KI, Brown R. Artificial sweetener use among children: epidemiology, recommendations, metabolic outcomes, and future directions. Pediatr Clin North Am. 2011;58:1467–80 xi.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yang Q: Gain weight by “going diet?” Artificial sweeteners and the neurobiology of sugar cravings: Neuroscience 2010. Yale J Biol Med 2010, 83:101-108.

  10. Fowler SP, Williams K, Hazuda HP. Diet Soda Intake Is Associated with Long-Term Increases in Waist Circumference in a Biethnic Cohort of Older Adults: The San Antonio Longitudinal Study of Aging. J Am Geriatr Soc. 2015;63:708–15.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fowler SP, Williams K, Resendez RG, Hunt KJ, Hazuda HP, Stern MP. Fueling the obesity epidemic? Artificially sweetened beverage use and long-term weight gain. Obesity (Silver Spring). 2008;16:1894–900.

    Article  Google Scholar 

  12. O’Connor L, Imamura F, Lentjes M, Khaw K, Wareham N, Forouhi N: Prospective associations and population impact of sweet beverage intake and type 2 diabetes, and effects of substitutions with alternative beverages. Diabetologia 2015, 58:1474-1483.

  13. 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;27:1120–6.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514:181–6.

    CAS  PubMed  Google Scholar 

  16. Palmnas MS, Cowan TE, Bomhof MR, Su J, Reimer RA, Vogel HJ, Hittel DS, Shearer J. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PLoS One. 2014;9:e109841.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A. 2008;71:1415–29.

    Article  CAS  PubMed  Google Scholar 

  18. 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;233:1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Swithers SE, Davidson TL. A role for sweet taste: calorie predictive relations in energy regulation by rats. Behav Neurosci. 2008;122:161–73.

    Article  PubMed  Google Scholar 

  20. Rogers PJ, Hogenkamp PS, de Graaf C, Higgs S, Lluch A, Ness AR, Penfold C, Perry R, Putz P, Yeomans MR, Mela DJ. Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies. Int J Obes (Lond). 2015. doi:10.1038/ijo.2015.177.

    Google Scholar 

  21. de Ruyter JC, Olthof MR, Seidell JC, Katan MB. A trial of sugar-free or sugar-sweetened beverages and body weight in children. N Engl J Med. 2012;367:1397–406.

    Article  PubMed  Google Scholar 

  22. Ebbeling CB, Feldman HA, Chomitz VR, Antonelli TA, Gortmaker SL, Osganian SK, Ludwig DS. A randomized trial of sugar-sweetened beverages and adolescent body weight. N Engl J Med. 2012;367:1407–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Frey GH. Use of aspartame by apparently healthy children and adolescents. J Toxicol Environ Health. 1976;2:401–15.

    Article  CAS  PubMed  Google Scholar 

  24. Mennella JA, Bobowski NK. The sweetness and bitterness of childhood: Insights from basic research on taste preferences. Physiol Behav. 2015;152:502–7.

    Article  CAS  PubMed  Google Scholar 

  25. Mojet J, Heidema J, Christ-Hazelhof E. Taste perception with age: generic or specific losses in supra-threshold intensities of five taste qualities? Chem Senses. 2003;28:397–413.

    Article  PubMed  Google Scholar 

  26. Zhang GH, Chen ML, Liu SS, Zhan YH, Quan Y, Qin YM, Deng SP: Effects of mother’s dietary exposure to acesulfame-K in Pregnancy or lactation on the adult offspring’s sweet preference. Chem Senses 2011, 36:763-770.

  27. Blackburn 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;65:409–18.

    CAS  PubMed  Google Scholar 

  28. Tordoff MG, Alleva AM. Effect of drinking soda sweetened with aspartame or high-fructose corn syrup on food intake and body weight. Am J Clin Nutr. 1990;51:963–9.

    CAS  PubMed  Google Scholar 

  29. Maersk M, Belza A, Stodkilde-Jorgensen H, Ringgaard S, Chabanova E, Thomsen H, Pedersen SB, Astrup A, Richelsen B. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Am J Clin Nutr. 2012;95:283–9.

    Article  CAS  PubMed  Google Scholar 

  30. Raben A, Vasilaras TH, Moller AC, Astrup A. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10 wk. of supplementation in overweight subjects. Am J Clin Nutr. 2002;76:721–9.

    CAS  PubMed  Google Scholar 

  31. Tate DF, Turner-McGrievy G, Lyons E, Stevens J, Erickson K, Polzien K, Diamond M, Wang X, Popkin B. Replacing caloric beverages with water or diet beverages for weight loss in adults: main results of the Choose Healthy Options Consciously Everyday (CHOICE) randomized clinical trial. Am J Clin Nutr. 2012;95:555–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S. Sucralose affects glycemic and hormonal responses to an oral glucose load. Diabetes Care. 2013;36:2530–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brown RJ, Walter M, Rother KI. Ingestion of diet soda before a glucose load augments glucagon-like peptide-1 secretion. Diabetes Care. 2009;32:2184–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fushan AA, Simons CT, Slack JP, Manichaikul A, Drayna D. Allelic polymorphism within the TAS1R3 promoter is associated with human taste sensitivity to sucrose. Curr Biol. 2009;19:1288–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Joseph PV, Reed DR, Mennella JA. Individual Differences Among Children in Sucrose Detection Thresholds: Relationship With Age, Gender, and Bitter Taste Genotype. Nurs Res. 2016;65:3–12.

    PubMed  Google Scholar 

  36. Suez J, Korem T, Zilberman-Schapira G, Segal E, Elinav E. Non-caloric artificial sweeteners and the microbiome: findings and challenges. Gut Microbes. 2015;6:149–55.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto JM, Kennedy S, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.

    Article  PubMed  Google Scholar 

  38. Wu H, Tremaroli V, Backhed F. Linking Microbiota to Human Diseases: A Systems Biology Perspective. Trends Endocrinol Metab. 2015;26:758–70.

    Article  CAS  PubMed  Google Scholar 

  39. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.

    Article  PubMed  Google Scholar 

  40. Haro C, Garcia-Carpintero S, Alcala-Diaz JF, Gomez-Delgado F, Delgado-Lista J, Perez-Martinez P, Rangel Zuniga OA, Quintana-Navarro GM, Landa BB, Clemente JC, et al. The gut microbial community in metabolic syndrome patients is modified by diet. J Nutr Biochem. 2016;27:27–31.

    Article  CAS  PubMed  Google Scholar 

  41. Leone V, Gibbons SM, Martinez K, Hutchison AL, Huang EY, Cham CM, Pierre JF, Heneghan AF, Nadimpalli A, Hubert N, et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe. 2015;17:681–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vrieze A, Holleman F, Zoetendal EG, de Vos WM, Hoekstra JB, Nieuwdorp M. The environment within: how gut microbiota may influence metabolism and body composition. Diabetologia. 2010;53:606–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Piernas C, Tate DF, Wang X, Popkin BM. Does diet-beverage intake affect dietary consumption patterns? Results from the Choose Healthy Options Consciously Everyday (CHOICE) randomized clinical trial. Am J Clin Nutr. 2013;97:604–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sorensen LB, Vasilaras TH, Astrup A, Raben A. Sucrose compared with artificial sweeteners: a clinical intervention study of effects on energy intake, appetite, and energy expenditure after 10 wk. of supplementation in overweight subjects. Am J Clin Nutr. 2014;100:36–45.

    Article  PubMed  Google Scholar 

  45. Reid M, Hammersley R, Hill AJ, Skidmore P. Long-term dietary compensation for added sugar: effects of supplementary sucrose drinks over a 4-week period. Br J Nutr. 2007;97:193–203.

    Article  CAS  PubMed  Google Scholar 

  46. Maki KC, Curry LL, Reeves MS, Toth PD, McKenney JM, Farmer MV, Schwartz SL, Lubin BC, Boileau AC, Dicklin MR, et al. Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus. Food Chem Toxicol. 2008;46(Suppl 7):S47–53.

    Article  CAS  PubMed  Google Scholar 

  47. Kanders 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.

    Article  PubMed  Google Scholar 

  48. Cooper PL, Wahlqvist ML, Simpson RW. Sucrose versus saccharin as an added sweetener in non-insulin-dependent diabetes: short- and medium-term metabolic effects. Diabet Med. 1988;5:676–80.

    Article  CAS  PubMed  Google Scholar 

  49. Colagiuri S, Miller JJ, Edwards RA. Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus. Am J Clin Nutr. 1989;50:474–8.

    CAS  PubMed  Google Scholar 

  50. Peters JC, Wyatt HR, Foster GD, Pan Z, Wojtanowski AC, Vander Veur SS, Herring SJ, Brill C, Hill JO. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity (Silver Spring). 2014;22:1415–21.

    Article  Google Scholar 

  51. United States Department of Agriculture: Sugar and Sweeteners Outlook. 2012. http://www.ers.usda.gov/Publications/SSS/

  52. Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, Spencer PS, Waddell WJ, Walker R, Williams GM. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev. Toxicol. 2007;37:629–727.

    Article  CAS  PubMed  Google Scholar 

  53. Wilson LA, Wilkinson K, Crews HM, Davies AM, Dick CS, Dumsday VL. Urinary monitoring of saccharin and acesulfame-K as biomarkers of exposure to these additives. Food Addit Contam. 1999;16:227–38.

    Article  CAS  PubMed  Google Scholar 

  54. Schiffman SS, Rother KI. Sucralose, a synthetic organochlorine sweetener: overview of biological issues. J Toxicol Environ Health B Crit Rev. 2013;16:399–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Anton SD, Martin CK, Han H, Coulon S, Cefalu WT, Geiselman P, Williamson DA. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite. 2010;55:37–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brown RJ, Walter M, Rother KI. Effects of diet soda on gut hormones in youths with diabetes. Diabetes Care. 2012;35:959–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Black RM, Leiter LA, Anderson GH. Consuming aspartame with and without taste: differential effects on appetite and food intake of young adult males. Physiol Behav. 1993;53:459–66.

    Article  CAS  PubMed  Google Scholar 

  58. Rogers PJ, Burley VJ, Alikhanizadeh LA, Blundell JE. Postingestive inhibition of food intake by aspartame: importance of interval between aspartame administration and subsequent eating. Physiol Behav. 1995;57:489–93.

    Article  CAS  PubMed  Google Scholar 

  59. Hall WL, Millward DJ, Rogers PJ, Morgan LM. Physiological mechanisms mediating aspartame-induced satiety. Physiol Behav. 2003;78:557–62.

    Article  CAS  PubMed  Google Scholar 

  60. Rogers PJ, Keedwell P, Blundell JE. Further analysis of the short-term inhibition of food intake in humans by the dipeptide L-aspartyl-L-phenylalanine methyl ester (aspartame). Physiol Behav. 1991;49:739–43.

    Article  CAS  PubMed  Google Scholar 

  61. Rogers PJ, Pleming HC, Blundell JE. Aspartame ingested without tasting inhibits hunger and food intake. Physiol Behav. 1990;47:1239–43.

    Article  CAS  PubMed  Google Scholar 

  62. Brown RJ, Rother KI. Non-nutritive sweeteners and their role in the gastrointestinal tract. J Clin Endocrinol Metab. 2012;97:2597–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Grotz VL, Henry RR, McGill JB, Prince MJ, Shamoon H, Trout JR, Pi-Sunyer FX. Lack of effect of sucralose on glucose homeostasis in subjects with type 2 diabetes. J Am Diet Assoc. 2003;103:1607–12.

    Article  PubMed  Google Scholar 

  64. Ma J, Chang J, Checklin HL, Young RL, Jones KL, Horowitz M, Rayner CK. Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects. Br J Nutr. 2010;104:803–6.

    Article  CAS  PubMed  Google Scholar 

  65. Collison KS, Makhoul NJ, Zaidi MZ, Al-Rabiah R, Inglis A, Andres BL, Ubungen R, Shoukri M, Al-Mohanna FA. Interactive effects of neonatal exposure to monosodium glutamate and aspartame on glucose homeostasis. Nutr Metab (Lond). 2012;9:58.

    Article  CAS  Google Scholar 

  66. Stern SB, Bleicher SJ, Flores A, Gombos G, Recitas D, Shu J. Administration of aspartame in non-insulin-dependent diabetics. J Toxicol Environ Health. 1976;2:429–39.

    Article  CAS  PubMed  Google Scholar 

  67. American Academy of Pediatrics SoB. Breastfeeding and the use of human milk. Pediatrics. 2012;129:e827–41.

    Article  Google Scholar 

  68. Mitsutomi K, Masaki T, Shimasaki T, Gotoh K, Chiba S, Kakuma T, Shibata H. Effects of a nonnutritive sweetener on body adiposity and energy metabolism in mice with diet-induced obesity. Metabolism. 2014;63:69–78.

    Article  CAS  PubMed  Google Scholar 

  69. Sylvetsky AC, Greenberg M, Zhao X, Rother KI. What Parents Think about Giving Nonnutritive Sweeteners to Their Children: A Pilot Study. Int J Pediatr. 2014;2014:819872.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Sylvetsky AC, Dietz WH. Nutrient-content claims–guidance or cause for confusion? N Engl J Med. 2014;371:195–8.

    Article  PubMed  Google Scholar 

  71. Pepino MY, Bourne C. Non-nutritive sweeteners, energy balance, and glucose homeostasis. Curr Opin Clin Nutr Metab Care. 2011;14:391–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Research and Markets: Global Food Sweetener Market- Growth, Trends, Forecast for the Period (2015-2020). 2015. http://www.researchandmarkets.com/reports/3261777/global-food-sweetener-market-growth-trends#pos-16. Accessed 15 Jan 2016.

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Acknowledgments

This work was funded in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.

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  1. Department of Exercise and Nutrition Sciences, The George Washington University, 950 New Hampshire Avenue NW, Washington, DC, 20052, USA

    Allison C. Sylvetsky

  2. Section on Pediatric Diabetes and Metabolism, NIDDK, NIH, 9000 Rockville Pike, Building 10, Room 8C432A, Bethesda, MD, 20892, USA

    Allison C. Sylvetsky, Jenny E. Blau & Kristina I. Rother

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Sylvetsky, A.C., Blau, J.E. & Rother, K.I. Understanding the metabolic and health effects of low-calorie sweeteners: methodological considerations and implications for future research. Rev Endocr Metab Disord 17, 187–194 (2016). https://doi.org/10.1007/s11154-016-9344-5

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