Effects of Artificial Sweetener Consumption on Glucose Homeostasis and Its Association with Type 2 Diabetes and Obesity

Figures & data

Figure 1 Chemical structures of the approved artificial sweeteners.

Table 1 Clinical Trials Investigating the Effect of AS Consumption on Glucose Homoeostasis

Authors and Year	Study Design	Population and Age	Parameters	Findings
Anton et al^Citation14 2010	Single-blind randomized crossover study	19 participants with normal weight and 12 obese subjects (18–49 years)	Glucose Insulin Insulinogenic index	Reduction in blood glucose and insulin levels with stevia consumption compared to sucrose Lower blood glucose levels with aspartame consumption at 20 min compared to sucrose Higher insulinogenic index with aspartame consumption at 1 hour
Ma et al^Citation41 2010	Single-blind randomized crossover study	10 healthy normal weight subjects (25–29 years)	Glucose GLP-1	Intraduodenal infusion of sucralose did not change glucose intestinal absorption or GLP-1 secretion compared to control infusion
Brown et al^Citation42 2011	Double-blind randomized crossover study	8 healthy normal weight women (19–24 years)	Glucose Insulin Glucagon Ghrelin	No significant changes were described with sucralose consumption compared to water
Ford et al^Citation43 2011	Single-blind randomized crossover study	8 healthy normal weight subjects (22–27 years)	Glucose Insulin GLP-1 PYY	Sucralose consumption did not change any variables compared to water
Steinert et al^Citation44 2011	Randomized crossover study (no blinding)	12 healthy normal weight subjects (22–24 years)	Glucose Insulin GLP-1 PYY Ghrelin	No significant differences were observed in any of the parameters following consumption of aspartame, acesulfame-k, or sucralose compared to water
Wu et al^Citation45 2012	Single-blind randomized crossover study	10 healthy obese subjects (25–33 years)	Glucose Insulin GLP-1 GIP	Sucralose consumption had no effects on any parameters
Maersk et al^Citation16 2012	Randomized crossover study (no blinding)	24 healthy obese subjects (20–50 years)	Glucose Insulin GLP-1 GIP Ghrelin	Aspartame consumption did not change any variables
Brown et al^Citation11 2012	Randomized crossover study (no blinding)	44 subjects divided into 3 groups: 25 healthy controls, 10 with T2D, and 9 with type 1 diabetes (12–25 years)	Glucose GLP-1 GIP PYY C-peptide	Diet soda consumption before a glucose load increased GLP-1 secretion in healthy and type 1 diabetic individuals compared to carbonated water No changes in other parameters
Stellingwerff et al^Citation46 2013	Double-blind randomized crossover study	23 healthy normal weight men (22–36 years)	Glucose Insulin	Sucralose consumption immediately before exercise had no effects on glucose and insulin concentrations during exercise
Pepino et al^Citation10 2013	Randomized crossover study (no blinding)	17 healthy obese (34–36 years)	Glucose Insulin Insulin sensitivity Insulin clearance glucagon GLP-1 GIP C-peptide	Sucralose consumption showed higher glucose, insulin, and C-peptide concentration, with a reduction in insulin sensitivity and insulin clearance No differences were found in GIP, GLP-1, and glucagon
Olalde-Mendoza et al^Citation15 2013	Randomized study (no blinding)	80 obese individuals with T2D (40–58 years)	Capillary glucose	Diet soda consumption had no effects on capillary glucose concentrations
Bryant et al^Citation47 2014	Randomized crossover study (no blinding)	10 normal weight subjects (18–24 years)	Glucose	Consumption of saccharine, aspartame, or acesulfame-k in combination with glucose did not change blood glucose concentrations compared to glucose alone
Temizkan et al^Citation9 2015	Single-blind randomized crossover design	8 newly diagnosed type 2 diabetic patients (51.5±9.2 years) and 8 healthy obese subjects (45.0±4.1 years)	Glucose Insulin GLP-1 C-peptide	Sucralose consumption was associated with lower glucose and higher GLP-1 concentrations compared to water consumption in healthy individuals No differences in sucralose or aspartame on insulin and C-peptide
Boyle et al^Citation48 2016	Single-blind randomized crossover design	40 healthy normal weight and obese subjects (50–65 years)	Capillary glucose Interstitial glucose	Sucralose consumption had no effects on capillary or interstitial glucose concentrations
Dhillon et al^Citation49 2017	Single-blind randomized crossover design	64 obese subjects (18–50 years)	Glucose Cephalic phase insulin response	Significant changes in blood glucose concentration with sucralose consumption compared to control Significant cephalic phase insulin response following sucralose consumption
Tey et al^Citation50 2018	Single-blind randomized crossover study	32 healthy normal weight men (21–50 years)	Postprandial glucose	Consumption of low-calorie sweeteners was associated with a lower postprandial glucose concentration compared to high-calorie sweeteners
Crézé et al^Citation51 2018	Randomized crossover study (no blinding)	18 healthy normal weight subjects (age not provided)	Glucose Insulin Ghrelin	Consumption of artificial sweetened beverages was associated with lower plasma glucose and insulin concentration compared to sucrose-sweetened beverages Plasma ghrelin showed higher values in artificially sweetened beverages compared to sucrose-sweetened beverages
Farhat et al^Citation52 2019	Single-blind randomized crossover study	30 healthy normal weight and obese subjects (16–36 years)	Postprandial glucose	Stevia consumption had no effect on postprandial glucose
Gómez-Arauz et al^Citation53 2019	Randomized placebo-controlled trial	45 participants divided into 2 groups: 20 controls (21.55±2.18 years) and 25 who ingested sucralose (22±2.99 years)	Glucose Insulin	Sucralose consumption showed higher serum insulin levels at 30, 45, and 180 min following oral glucose tolerance test. No differences were observed for blood glucose levels
Nichol et al^Citation54 2020	Randomized crossover study (no blinding)	10 healthy normal weight and 11 healthy obese subjects (23–33 years)	Glucose Insulin C-peptide GIP	Sucralose consumption elevated plasma glucose by 30±10% in lean and obese subjects compared to water Insulin levels reduced within 20–40 min of the oral glucose tolerance test in lean subjects and increased within 90–120 min in obese subjects C-peptide and GIP did not show significant differences
Bueno-Hernández et al^Citation55 2020	Randomized double-blind placebo-controlled trial	137 subjects divided into 3 groups: a) subjects receiving water as controls, b) subjects receiving 48 mg sucralose, and c) subjects receiving 96 mg sucralose	Glucose insulin	Sucralose intake for 10 weeks resulted in: higher insulin concentrations at 0, 30, 105 and 120 min following oral glucose tolerance test in the group receiving 48 mg sucralose higher blood glucose at −15, 0, and 120 min in the group receiving 48 mg sucralose higher area under the curve (AUC) of insulin in groups receiving 48 and 96 mg sucralose

Table 2 Observational Cohort Studies Investigating the Association Between AS Consumption and Risk of Development of T2D

Authors and Year	Number and Age of Participants	Follow-up Period	Main Outcomes
Palmer et al^Citation56 2008	43,960 women (21–69 years)	4 years	No association was found between diet soft drink consumption and incidence of T2D
Nettleton et al^Citation22 2009	5011 adults (45–84 years)	7 years	Daily diet soda intake was associated with a 67% higher risk of developing T2D
de Koning et al^Citation19 2011	40,389 male health professionals (40–75 years)	20 years	Relationship of artificially sweetened beverages consumption and risk of T2D was observed in the age-adjusted analysis. However, in the multivariate-adjusted analysis no relationship was found
Bhupathiraju et al^Citation24 2013	74,749 female nurses (30–55 years)	24 years	Significant association was observed between caffeine-free artificially sweetened soft drinks and incidence of T2D after multivariable adjustment for BMI and energy intake
Bhupathiraju et al^Citation24 2013	39,059 healthcare professional men (40–75 years)	22 years	No association was found between caffeinated or non-caffeinated artificially sweetened beverage intake and risk of T2D after multivariable adjustment
The InterAct Consortium^Citation25 2013	34,234 adults (39–69 years)	16 years	No relationship was observed between artificially sweetened beverage intake and the incidence of T2D after multivariable adjustment for BMI and energy intake
Fagherazzi et al^Citation21 2013	66,118 women (46–59 years)	14 years	Significant association was described between high consumption of artificially sweetened beverages (>630 mL/week) and the development of T2D
Sakurai et al^Citation23 2014	2037 men (35–55 years)	7 years	Daily consumption of diet soda was positively associated with increased risk of T2D after multivariable adjustment
O’Connor et al^Citation26 2015	24,653 adults (40–79 years)	10.8 years	Significant association was found between artificially sweetened beverage consumption and incidence of T2D. Yet, after adjusting for adiposity (BMI and waist circumference) this became insignificant
Ma et al^Citation57 2016	1685 adults (43–61 years)	14 years	No association was found between diet soda intake and increased prediabetes risk
Fagherazzi et al^Citation20 2017	61,440 women (46–59 years)	18 years	Significant association was observed between AS consumption in packets or tablets and development of T2D after adjustment for BMI
Huang et al^Citation58 2017	64,850 women (50–79 years)	8.4 years	Consumption of artificially sweetened beverages was associated with a 21% higher risk of developing T2D
Gardener et al^Citation59 2018	2019 adults (59–79 years)	11 years	Strong positive association was found between diet soda intake and the development of T2D. Yet, after adjusting for BMI this became null
Jensen et al^Citation60 2020	1359 adults (25–60 years)	8 years	No association was found between AS consumption and the risk of T2D

Anton SD, Martin CK, Han H, et al. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite. 2010;55(1):37–43. doi:10.1016/j.appet.2010.03.00920303371

 PubMed Web of Science ®Google Scholar

Ma J, Chang J, Checklin HL, et al. Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects. Br J Nutr. 2010;104(6):803–806. doi:10.1017/S000711451000132720420761

 PubMed Web of Science ®Google Scholar

Brown AW, Brown MMB, Onken KL, Beitz DC. Short-term consumption of sucralose, a nonnutritive sweetener, is similar to water with regard to select markers of hunger signaling and short-term glucose homeostasis in women. Nutr Res. 2011;31(12):882–888.22153513

 PubMed Web of Science ®Google Scholar

Ford H, Peters V, Martin N, et al. Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects. Eur J Clin Nutr. 2011;65(4):508–513. doi:10.1038/ejcn.2010.29121245879

 PubMed Web of Science ®Google Scholar

Steinert RE, Frey F, Töpfer A, Drewe J, Beglinger C. Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides. Br J Nutr. 2011;105(9):1320–1328.21255472

 PubMed Web of Science ®Google Scholar

Wu T, Zhao BR, Bound MJ, et al. Effects of different sweet preloads on incretin hormone secretion, gastric emptying, and postprandial glycemia in healthy humans. Am J Clin Nutr. 2012;95(1):78–83. doi:10.3945/ajcn.111.02154322158727

 PubMed Web of Science ®Google Scholar

Maersk M, Belza A, Holst JJ, et al. Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: a controlled trial. Eur J Clin Nutr. 2012;66(4):523–529. doi:10.1038/ejcn.2011.22322252107

 PubMed Web of Science ®Google Scholar

Brown RJ, Walter M, Rother KI. Effects of diet soda on gut hormones in youths with diabetes. Diabetes Care. 2012;35(5):959–964. doi:10.2337/dc11-242422410815

 PubMed Web of Science ®Google Scholar

Stellingwerff T, Godin J-P, Beaumont M, et al. Effects of pre-exercise sucralose ingestion on carbohydrate oxidation during exercise. Int J Sport Nutr Exerc Metab. 2013;23(6):584–592.23689036

 PubMed Web of Science ®Google Scholar

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(9):2530–2535. doi:10.2337/dc12-222123633524

 PubMed Web of Science ®Google Scholar

Olalde-Mendoza L, Moreno-González YE. Modification of fasting blood glucose in adults with diabetes mellitus type 2 after regular soda and diet soda intake in the state of Queretaro, Mexico. Arch Latinoam Nutr. 2013;63(2):142–147.24934070

 PubMed Web of Science ®Google Scholar

Bryant CE, Wasse LK, Astbury N, Nandra G, McLaughlin JT. Non-nutritive sweeteners: no class effect on the glycaemic or appetite responses to ingested glucose. Eur J Clin Nutr. 2014;68(5):629–631. doi:10.1038/ejcn.2014.1924595225

 PubMed Web of Science ®Google Scholar

Temizkan S, Deyneli O, Yasar M, et al. Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in patients with type 2 diabetes. Eur J Clin Nutr. 2015;69(2):162–166. doi:10.1038/ejcn.2014.20825271009

 PubMed Web of Science ®Google Scholar

Boyle NB, Lawton CL, Allen R, Croden F, Smith K, Dye L. No effects of ingesting or rinsing sucrose on depleted self-control performance. Physiol Behav. 2016;154:151–160. doi:10.1016/j.physbeh.2015.11.01926617402

 PubMed Web of Science ®Google Scholar

Dhillon J, Lee JY, Mattes RD. The cephalic phase insulin response to nutritive and low-calorie sweeteners in solid and beverage form. Physiol Behav. 2017;181:100–109. doi:10.1016/j.physbeh.2017.09.00928899680

 PubMed Web of Science ®Google Scholar

Tey SL, Salleh N, Henry CJ, Forde CG. Effects of consuming preloads with different energy density and taste quality on energy intake and postprandial blood glucose. Nutrients. 2018;10(2):161. doi:10.3390/nu10020161

 Web of Science ®Google Scholar

Crézé C, Candal L, Cros J, et al. The impact of caloric and non-caloric sweeteners on food intake and brain responses to food: a randomized crossover controlled trial in healthy humans. Nutrients. 2018;10(5):615. doi:10.3390/nu10050615

 Web of Science ®Google Scholar

Farhat G, Berset V, Moore L. Effects of stevia extract on postprandial glucose response, satiety and energy intake: a three-arm crossover trial. Nutrients. 2019;11(12):3036. doi:10.3390/nu11123036

 Web of Science ®Google Scholar

Gómez-Arauz AY, Bueno-Hernández N, Palomera LF, et al. A single 48 mg sucralose sip unbalances monocyte subpopulations and stimulates insulin secretion in healthy young adults. J Immunol Res. 2019;2019.

 Web of Science ®Google Scholar

Nichol AD, Salame C, Rother KI, Pepino MY. Effects of sucralose ingestion versus sucralose taste on metabolic responses to an oral glucose tolerance test in participants with normal weight and obesity: a randomized crossover trial. Nutrients. 2020;12(1):29. doi:10.3390/nu12010029

 Web of Science ®Google Scholar

Bueno-Hernández N, Esquivel-Velázquez M, Alcántara-Suárez R, et al. Chronic sucralose consumption induces elevation of serum insulin in young healthy adults: a randomized, double blind, controlled trial. Nutr J. 2020;19:1–12.31901246

 PubMed Web of Science ®Google Scholar

Palmer JR, Boggs DA, Krishnan S, Hu FB, Singer M, Rosenberg L. Sugar-sweetened beverages and incidence of type 2 diabetes mellitus in African American women. Arch Intern Med. 2008;168(14):1487–1492. doi:10.1001/archinte.168.14.148718663160

 PubMedGoogle Scholar

Nettleton JA, Lutsey PL, Wang Y, Lima JA, Michos ED, Jacobs 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(4):688–694. doi:10.2337/dc08-179919151203

 PubMed Web of Science ®Google Scholar

De Koning L, Malik VS, Rimm EB, Willett WC, Hu FB. Sugar-sweetened and artificially sweetened beverage consumption and risk of type 2 diabetes in men. Am J Clin Nutr. 2011;93(6):1321–1327. doi:10.3945/ajcn.110.00792221430119

 PubMed Web of Science ®Google Scholar

Bhupathiraju SN, Pan A, Malik VS, et al. Caffeinated and caffeine-free beverages and risk of type 2 diabetes. Am J Clin Nutr. 2013;97(1):155–166.23151535

 PubMed Web of Science ®Google Scholar

InterAct Consortium. Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct. Diabetologia. 2013;56(7):1520–1530. doi:10.1007/s00125-013-2899-823620057

 PubMed Web of Science ®Google Scholar

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 epidémiologique auprès des femmes de la mutuelle générale de l’education nationale–European prospective investigation into cancer and nutrition cohort. Am J Clin Nutr. 2013;97(3):517–523. doi:10.3945/ajcn.112.05099723364017

 PubMed Web of Science ®Google Scholar

Sakurai M, Nakamura K, Miura K, et al. Sugar-sweetened beverage and diet soda consumption and the 7-year risk for type 2 diabetes mellitus in middle-aged Japanese men. Eur J Nutr. 2014;53(1):251–258. doi:10.1007/s00394-013-0523-923575771

 PubMed Web of Science ®Google Scholar

O’Connor L, Imamura F, Lentjes MA, Khaw K-T, Wareham NJ, Forouhi NG. Prospective associations and population impact of sweet beverage intake and type 2 diabetes, and effects of substitutions with alternative beverages. Diabetologia. 2015;58(7):1474–1483. doi:10.1007/s00125-015-3572-125944371

 PubMed Web of Science ®Google Scholar

Ma J, Jacques PF, Meigs JB, et al. Sugar-sweetened beverage but not diet soda consumption is positively associated with progression of insulin resistance and prediabetes. J Nutr. 2016;146(12):2544–2550. doi:10.3945/jn.116.23404727934644

 PubMed Web of Science ®Google Scholar

Fagherazzi G, Gusto G, Affret A, et al. Chronic consumption of artificial sweetener in packets or tablets and type 2 diabetes risk: evidence from the E3N-European prospective investigation into cancer and nutrition study. Ann Nutr Metab. 2017;70(1):51–58. doi:10.1159/000458769

 Web of Science ®Google Scholar

Huang M, Quddus A, Stinson L, et al. Artificially sweetened beverages, sugar-sweetened beverages, plain water, and incident diabetes mellitus in postmenopausal women: the prospective women’s health initiative observational study. Am J Clin Nutr. 2017;106(2):614–622. doi:10.3945/ajcn.116.14539128659294

 PubMed Web of Science ®Google Scholar

Gardener H, Moon YP, Rundek T, Elkind MS, Sacco RL. Diet Soda and sugar-sweetened soda consumption in relation to incident diabetes in the Northern Manhattan study. Curr Dev Nutr. 2018;2(5):nzy008. doi:10.1093/cdn/nzy00829955723

 PubMed Web of Science ®Google Scholar

Jensen PN, Howard BV, Best LG, et al. Associations of diet soda and non-caloric artificial sweetener use with markers of glucose and insulin homeostasis and incident diabetes: the strong heart family study. Eur J Clin Nutr. 2020;74(2):322–327. doi:10.1038/s41430-019-0461-631253876

 PubMed Web of Science ®Google Scholar