TY - JOUR
AU - Mackay, Dylan, S
AB - Abstract Non-nutritive sweeteners are thought to be useful replacements for caloric sweeteners in sweet food and beverages, since the reduction in energy and carbohydrate intake may lead to health benefits stemming from weight management and glycemic control. However, the potential effects of non-nutritive sweeteners on glucose metabolism and gut hormones have not been determined definitively. Here, the available evidence of the effects of aspartame and sucralose consumption on glucose metabolism and gut hormones is reviewed. A majority of studies have found that consumption of aspartame or sucralose has no effect on concentrations of blood glucose, insulin, or gut hormones; however, 2 trials have shown that aspartame consumption affects glucose, insulin, and glucagon-like peptide 1 concentrations, while only a few trials have shown that sucralose consumption affects glucose, insulin, and glucagon-like peptide 1 concentrations. One study found higher glucose concentrations after sucralose consumption, while 3 studies found lower concentrations and 33 studies found no change in glucose concentrations. Moreover, only 4 studies reported increased concentrations of glucagon-like peptide 1. Three studies reported decreased insulin sensitivity following sucralose consumption, while 1 trial reported an increase in insulin sensitivity. In summary, the evidence from the clinical trials conducted to date is contradictory because of the different protocols used. aspartame, glucose metabolism, low-calorie sweeteners, non-nutritive sweeteners, sucralose INTRODUCTION The consumption of sugar- and energy-dense food and beverages has been associated with many negative health outcomes, including weight gain, obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, and cardiovascular disease.1–3 As a result, non-nutritive sweeteners (NNSs) have become popular sugar substitutes in the food and beverage market globally. Their inclusion in frequently advertised zero- and low-calorie beverages, their affordability, and their integration into weight loss diets all contribute to their popularity.4,5 A recent National Health and Nutrition Examination Survey reported that approximately 48% of US adults consumed NNSs from multiple dietary sources from 2007 to 2012,6 which is higher than previously reported.7,8 The effect of NNS consumption on health is unclear, as mixed results are reported in the literature. Consumption of NNSs, mainly in the form of diet soda, has been associated with weight gain, as opposed to weight loss, and may increase appetite and food intake.5,9 In contrast, it has been shown that NNS-containing beverages, when compared with sugar-containing beverages, can be beneficial for maintaining body weight10 and decreasing cardiovascular disease and T2DM.11 Evidence of the effect of NNSs on glucose metabolism and gut hormones is still inconclusive. For example, Romo-Romo et al12 conducted a systematic review of 14 observational prospective studies, 28 clinical trials (1985–2015), and 2 meta-analyses to assess the effect of NNS consumption on glucose metabolism and appetite-stimulating gut hormones in adults. They concluded that the effect of NNS consumption on glucose metabolism was unclear.12 Moreover, the effects of NNSs on weight, metabolic health, glucose homeostasis, and glycemic responses are also uncertain.13–15 The aim of this narrative review is to summarize the available evidence regarding the effect of aspartame and sucralose on glucose metabolism. First, an overview of aspartame and sucralose absorption, metabolism, and excretion is provided, and then the possible mechanisms through which NNS consumption could influence glucose metabolism are examined. This is followed by a summary of the clinical trials on the effects of aspartame and sucralose on glucose metabolism. The objectives outlined here were achieved by searching the PubMed and PubMed Central databases, using different keywords and all possible combinations of keywords from the following 2 groups: (1) artificial sweeteners, non-nutritive sweeteners, nonnutritive sweetener, non nutritive sweetener, low calorie sweetener, low-calorie sweeteners, zero-calorie sweeteners, sucralose, aspartame, splenda, nutrasweet, equal, sugar twin, saccharin, stevia, neotame, acesulfame, diet soda, diet drink, and diet beverage; and (2) glucose tolerance, glycemic load, glycaemic load, glycemic responses, glucose load, blood glucose, oral glucose, oral ingestion, glucose metabolism, glucose homeostasis, glucose profiles, insulin, insulin sensitivity, GLP-1, glucagon-like peptide-1, GIP, incretin hormone, hormonal responses, clinical trials, and randomized clinical trial. Titles and abstracts of the articles recognized through the keyword search were retrieved for evaluation of the full text and were included in the review if they met all of the following criteria: (1) study designed as a randomized clinical trial (RCT); (2) study conducted in human participants; (3) intervention designed to administer NNSs orally, intragastrically, or intraduodenally, alone or in combination with beverages or food; (4) outcome assessed was the effect of NNS consumption on glucose metabolism; and (5) articles were published in English in a peer-reviewed publication. TYPES OF NON-NUTRITIVE SWEETENERS Non-nutritive sweeteners, also called zero-calorie or low-calorie sweeteners, can be extracted from natural sources or synthesized. As chemosensory compounds, they have the ability to produce an intensely sweet taste with few or no calories. They are often used at concentrations far lower than those of caloric sweeteners. Their intense sweetness without calories makes them very popular in the food and beverage market, as they have the potential to aid in the control of body weight and glycemia.4,5 To date, several NNSs have been approved by the US Food and Drug Administration (FDA), including 7 artificial ones (aspartame, sucralose, neotame, saccharin, acesulfame potassium [acesulfame K], neotame, and advantame) and 2 natural ones (steviol glycosides and Luo Han Guo [monk fruit] extract) (Table 1).16 In Canada, approved NNSs include aspartame, sucralose, neotame, acesulfame K, steviol glycosides, and monk fruit extract.17 This review examines aspartame and sucralose, the most frequently consumed artificial sweeteners.18 Table 1 Currently approved non-nutritive sweeteners and their uses Generic chemical name . Trade name . Year of discovery . Known metabolites . Multiplier of sweetness intensity (compared with table sugar, ie, sucrose) . Acceptable daily intake, USA (milligrams per kilogram of body weight per day) . Acceptable daily intake, Canada (milligrams per kilogram of body weight per day) . Common uses . Acesulfame potassium Sunett, Sweet One 1967 None (not metabolized) 200 times 15 15 Frozen desserts, candies, beverages, baked goods Aspartame Equal, NutraSweet, Sugar Twin 1965 Methanol, aspartic acid, phenylalanine 200 times 50 40 Table top sweetener, chewing gum, breakfast cereals Advantame – 2014 (FDA approved) – 20 000 times 32.8 N/A General-purpose sweetener, flavor enhancer, baked goods Neotame Newtame 2002 (FDA approved) Methanol (de-esterified derivative) 7000–13 000 times 0.3 N/A Baked goods Saccharin Sweet’N Low, Sweet Twin, Necta Sweet 1879 o-sulfamoylbenzoic acid 200–700 times 5 5 (banned in 1970s, then approved in 2014) Beverages, fruit juice drinks, cooking, tabletop use Sucralose Splenda 1976 None (not metabolized) ≈ 600 times 5 9 Baked goods, beverages, chewing gum, gelatins, frozen dairy desserts Steviol glycosides Truvia, Enliten, Pure Via 1955 – 200–400 times 4 N/A Baked goods, soft drinks Luo Han Guo fruit extract Nectresse, PureLo, Monk Fruit in the Raw 13th century – 100–250 times Not specified N/A Food, beverages, baked goods, desserts, and candies Generic chemical name . Trade name . Year of discovery . Known metabolites . Multiplier of sweetness intensity (compared with table sugar, ie, sucrose) . Acceptable daily intake, USA (milligrams per kilogram of body weight per day) . Acceptable daily intake, Canada (milligrams per kilogram of body weight per day) . Common uses . Acesulfame potassium Sunett, Sweet One 1967 None (not metabolized) 200 times 15 15 Frozen desserts, candies, beverages, baked goods Aspartame Equal, NutraSweet, Sugar Twin 1965 Methanol, aspartic acid, phenylalanine 200 times 50 40 Table top sweetener, chewing gum, breakfast cereals Advantame – 2014 (FDA approved) – 20 000 times 32.8 N/A General-purpose sweetener, flavor enhancer, baked goods Neotame Newtame 2002 (FDA approved) Methanol (de-esterified derivative) 7000–13 000 times 0.3 N/A Baked goods Saccharin Sweet’N Low, Sweet Twin, Necta Sweet 1879 o-sulfamoylbenzoic acid 200–700 times 5 5 (banned in 1970s, then approved in 2014) Beverages, fruit juice drinks, cooking, tabletop use Sucralose Splenda 1976 None (not metabolized) ≈ 600 times 5 9 Baked goods, beverages, chewing gum, gelatins, frozen dairy desserts Steviol glycosides Truvia, Enliten, Pure Via 1955 – 200–400 times 4 N/A Baked goods, soft drinks Luo Han Guo fruit extract Nectresse, PureLo, Monk Fruit in the Raw 13th century – 100–250 times Not specified N/A Food, beverages, baked goods, desserts, and candies Abbreviation: NA, not applicable. Open in new tab Table 1 Currently approved non-nutritive sweeteners and their uses Generic chemical name . Trade name . Year of discovery . Known metabolites . Multiplier of sweetness intensity (compared with table sugar, ie, sucrose) . Acceptable daily intake, USA (milligrams per kilogram of body weight per day) . Acceptable daily intake, Canada (milligrams per kilogram of body weight per day) . Common uses . Acesulfame potassium Sunett, Sweet One 1967 None (not metabolized) 200 times 15 15 Frozen desserts, candies, beverages, baked goods Aspartame Equal, NutraSweet, Sugar Twin 1965 Methanol, aspartic acid, phenylalanine 200 times 50 40 Table top sweetener, chewing gum, breakfast cereals Advantame – 2014 (FDA approved) – 20 000 times 32.8 N/A General-purpose sweetener, flavor enhancer, baked goods Neotame Newtame 2002 (FDA approved) Methanol (de-esterified derivative) 7000–13 000 times 0.3 N/A Baked goods Saccharin Sweet’N Low, Sweet Twin, Necta Sweet 1879 o-sulfamoylbenzoic acid 200–700 times 5 5 (banned in 1970s, then approved in 2014) Beverages, fruit juice drinks, cooking, tabletop use Sucralose Splenda 1976 None (not metabolized) ≈ 600 times 5 9 Baked goods, beverages, chewing gum, gelatins, frozen dairy desserts Steviol glycosides Truvia, Enliten, Pure Via 1955 – 200–400 times 4 N/A Baked goods, soft drinks Luo Han Guo fruit extract Nectresse, PureLo, Monk Fruit in the Raw 13th century – 100–250 times Not specified N/A Food, beverages, baked goods, desserts, and candies Generic chemical name . Trade name . Year of discovery . Known metabolites . Multiplier of sweetness intensity (compared with table sugar, ie, sucrose) . Acceptable daily intake, USA (milligrams per kilogram of body weight per day) . Acceptable daily intake, Canada (milligrams per kilogram of body weight per day) . Common uses . Acesulfame potassium Sunett, Sweet One 1967 None (not metabolized) 200 times 15 15 Frozen desserts, candies, beverages, baked goods Aspartame Equal, NutraSweet, Sugar Twin 1965 Methanol, aspartic acid, phenylalanine 200 times 50 40 Table top sweetener, chewing gum, breakfast cereals Advantame – 2014 (FDA approved) – 20 000 times 32.8 N/A General-purpose sweetener, flavor enhancer, baked goods Neotame Newtame 2002 (FDA approved) Methanol (de-esterified derivative) 7000–13 000 times 0.3 N/A Baked goods Saccharin Sweet’N Low, Sweet Twin, Necta Sweet 1879 o-sulfamoylbenzoic acid 200–700 times 5 5 (banned in 1970s, then approved in 2014) Beverages, fruit juice drinks, cooking, tabletop use Sucralose Splenda 1976 None (not metabolized) ≈ 600 times 5 9 Baked goods, beverages, chewing gum, gelatins, frozen dairy desserts Steviol glycosides Truvia, Enliten, Pure Via 1955 – 200–400 times 4 N/A Baked goods, soft drinks Luo Han Guo fruit extract Nectresse, PureLo, Monk Fruit in the Raw 13th century – 100–250 times Not specified N/A Food, beverages, baked goods, desserts, and candies Abbreviation: NA, not applicable. Open in new tab Aspartame Aspartame (L-α-aspartyl-L-phenylalanine methyl ester), discovered in 1965, is a low-calorie, artificial, nonsaccharide sweetener used to sweeten food and drink products. Produced as a white crystalline powder, it has a sweet taste very similar to that of sucrose, which is why it is commonly used in food and beverages. Aspartame is approximately 200 times as sweet as sucrose; therefore, only very small amounts are needed to achieve a sweet taste intensity similar to that of sucrose.4,16 It is commonly sold as Equal, NutraSweet, or Sugar Twin. In the small intestine, digestive enzymes break aspartame down into methanol, phenylalanine, and aspartic acid. These metabolites are further broken down into formaldehyde and formic acid,19 each of which follows a natural metabolic pathway to be metabolized just as they would from other dietary sources. Aspartame is metabolized and absorbed quickly, which is why it is never found circulating in the blood.20,21 Unlike other NNSs, aspartame has some nutritive value when metabolized in the body: 1 g of aspartame provides approximately 4 kcal.22 The FDA and Health Canada have established acceptable daily intakes (ADIs) of 50 mg/kg of body weight (bw) per day and 40 mg/kg bw/d, respectively.16,17 The ADI is an estimate of the maximum amount of a food additive in food or beverages (expressed on the basis of body weight) that can be safely consumed on a daily basis over a person’s lifetime without any health risk to the consumer, including a 100-fold safety factor.23 Sucralose Sucralose was discovered in 1976. Sucralose is a disaccharide made from sucrose by a chemical process that replaces the hydroxyl groups on sucrose molecules with 3 chloride atoms.24 Sucralose is approximately 600 times sweeter than sucrose, with a pleasant sweet taste very similar to that of sucrose, which accounts for its use in a wide variety of food and beverages.4 Sucralose is sold under the brand name Splenda. It is generally thought that 11% to 27% of sucralose is absorbed in the intestines and is removed from the blood circulation by the kidneys and excreted in urine, while the remaining portion is excreted unchanged in feces.25 However, a recent animal study did not support the findings of early metabolic studies: Bornemann et al26 reported that acetylated sucralose metabolites accumulated in the urine and feces of rats after repeated administration for 40 days at an average dosage of 80.4 mg/kg/d. This dosage was within the normal range of the toxicological studies submitted in North America and other countries. Therefore, since this recent finding shows that ingested sucralose may not be excreted unchanged in feces and urine, the regulatory agencies might need to revisit the safety status of sucralose, which was based on early metabolic studies. Another animal study, in male rats, found that sucralose ingestion for 12 weeks increased the expression of the intestinal efflux transporters P-glycoprotein and cytochrome P450.27 These 2 transporters are involved in drug detoxification, suggesting the body might be treating sucralose as a toxin that needs to be removed from the body.27 An ADI, usually based on toxicological evaluations, is assigned to every food additive. The FDA and Health Canada have established ADIs of 5 mg/kg bw/d and 9 mg/kg bw/d, respectively, for sucralose.16,17 POSSIBLE MECHANISMS OF THE EFFECTS OF NON-NUTRITIVE SWEETENERS ON GLUCOSE METABOLISM Activation of oral sweet taste receptors, gut sweet taste receptors, and gut hormones To understand the physiological role of NNSs, it is important to understand the physiology of taste receptors. The focus here will be on the sweet taste, which allows the recognition of energy-rich nutrients. In brief, the tongue has various types of taste papillae, including the foliate, the fungiform, and the circumvallate papillae. Each taste papilla has hundreds of taste buds. The human tongue has different regions that are able to sense different tastes (sweet, bitter, sour, salty and savory) and carry out different functions. These regions all work together to perform their designated functions.28 Taste receptor cells are anatomical substrates in units that are grouped into taste buds, which are present across the papillae of the palate epithelium and the tongue. Sweet and umami (savory) taste processes are mediated by a family of 3 G protein-coupled receptors: T1R1, T1R2, and T1R3. These G protein-coupled receptors are grouped into heterodimeric receptor complexes.29 When T1R3 and T1R2 combine, they form a sweet taste receptor that responds to all different classes of sweet tastes, including those produced by NNSs (eg, aspartame and sucralose), natural caloric sugars (eg, glucose, fructose, and sucrose), sweet proteins (monellin and thaumatin), and D-amino acids as well as various other types of organic compounds.28 Activation of the oral sweet taste receptors in the mouth occurs when a sweet substance binds to T1R2/T1R3 receptors, leading to the release of α-gustducin, which activates the release of different signaling effectors, including phospholipase C β2, inositol, and diacylglycerol. Then, the transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is activated, which depolarizes the plasma membrane to allow for calcium entry. Upon activation of effector cells and taste cell depolarization, neuronal signals are sent to the brain to transmit a sweetness sensation.30 Interestingly, sweet taste receptors have also been found in the gastrointestinal tract, especially in the small intestine and colon, and on pancreatic β cells. Stimulation of the sweet taste receptors in the gastrointestinal tract activates an intracellular signaling pathway similar to that in the mouth,31 which leads to the upregulation of the sodium-dependent glucose cotransporter 1 (SGLT1), an intestinal glucose transporter that provides a major route for dietary glucose transportation from the intestine into enterocytes. Afterward, glucose transporter 2 (GLUT2) is activated on the basolateral membrane to facilitate the movement of glucose into the blood circulation.32,33 Accordingly, sweet taste receptors, whether they are in the mouth or in the gut, are important for recognizing and metabolizing different energy sources in the human body. Interestingly, SGLT1 likely plays a more important role in glucose absorption in the human intestine than GLUT2. In their study, Kim et al34 showed that the intestinal expression of SGLT1 was much higher in humans than in mice and rats, while intestinal expression of GLUT2 was higher in rats.34 Stimulation of the gut taste receptors T1R2 and T1R3 also leads to the release of incretin hormones, including glucagon-like protein 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP are gut-derived peptides that stimulate insulin secretion upon an increase in blood glucose concentrations.35–37 In vivo data on the effects of NNSs on glucose metabolism and gut hormone secretions are inconsistent. For example, Margolskee et al37 showed that mice supplied with regular sugar and NNS solutions for 2 weeks showed increased expression of SGLT1 and an increased absorptive capacity of glucose in the gastrointestinal tract.37 Moreover, Mace et al38 reported that artificial sweeteners could increase the glucose absorption rate in rats by enhancing apical GLUT2 insertion into enterocytes.38 By contrast, Saada et al39 reported a decrease in serum glucose in normal and diabetic rats and found no effect on insulin in the diabetic rats compared with other groups after administering sucralose (Splenda) at a concentration of 11 mg/kg by oral gavage for 6 weeks.39 Likewise, Fujita et al40 reported that different types of sweeteners, including sucralose, acesulfame K, stevia, and D-tryptophan, when administered to male rats by gastric gavage, caused no effect on glucose absorption or release of incretin hormones.40 Results from human trials are also conflicting. A few studies have reported that NNS consumption can increase GLP-1 in healthy participants without affecting blood glucose concentrations,41,42 while another study showed that NNS consumption decreased GLP-1 concentrations.43 However, other trials in humans found that NNSs cause changes in blood glucose concentrations without causing any changes in GLP-144–46 (Table 241–75). These contradictory findings from human trials may be attributable to the many variations in the study protocols used, including the type of NNS used, the route of administration, and the duration of previous and current exposures to NNSs. Table 2 Studies evaluating the effects of non-nutritive sweetener (NNS) consumption on glucose metabolism Reference . Study design . Population characteristics . Duration of intervention . Type of NNS used . Dose of NNS used and method of administration . Main outcomes . Mezitis et al (1996)47 Randomized crossover trial Patients with T1DM or T2DM; M and F; n = 26; age < 65 y Single dose Sucralose Participants received sucralose (1000-mg capsule) or placebo (cellulose capsule), followed by a meal Sucralose consumption, compared with placebo, had no effect on glucose or C-peptide levels Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F Study 1: n = 8; mean age 32 y; mean weight 70 kg Repeated daily dose for 17 d Sucralose Participants fasted before the intervention. Sucralose supplied in aqueous solution (5 mg/mL) Phase 1: day 1: 0 mg/kg/d; day 3: 1.0 mg/kg/d; day 5: 2.5 mg/kg/d; day 7: 5 mg/kg/d; day 9: 10.0 mg/kg/d. Phase 2: day 11–13: 2.0 mg/kg/d; day 14–17: 5.0 mg/kg/d; day 18–25: 0 mg/kg/d No effect on fasting glucose or insulin Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F, mean weight 71.5 kg Study 2, sucralose group: n = 77; mean age 34.6 y Study 2, control group: n = 31; mean age 33.9 y Repeated daily dose for 13 wk Sucralose Sucralose supplied in aqueous solution (5 mg/mL) and consumed twice daily for a total daily dose: Sucralose group: weeks 1–3: 125 mg/d; weeks 4–7: 250 mg/d, weeks 5–12: 500 mg/d Control group (fructose): weeks 1–13: 50 g/d No effect on fasting glucose or insulin Grotz et al (2003)49 Randomized, double-blinded, placebo-controlled trial Obese adults with T2DM; M and F; N = 136; age 31–70 y; mean BMI 31.6 kg/m2 Sucralose group: n = 67 Placebo group: n = 69 Repeated daily dose for 13 wk Follow-up: 4 wk Sucralose Sucralose group: 1 capsule containing sucralose (333.5 mg) supplied twice daily. Total daily intake was 667 mg Placebo group: 1 capsule containing cellulose, supplied twice daily Follow-up phase: 1 cellulose capsules, supplied daily No significant differences in plasma glucose, insulin, serum C-peptides, or HbA1c levels between sucralose and placebo groups over the entire study period Reyna et al (2003)50 Randomized, controlled clinical trial Adults with T2DM; M; mean age 45 ± 55 y Control group (ADA diet): n = 8; mean BMI 28.9 ± 2.0 kg/m2 Expermintal group (modified ADA diet): n = 8; mean BMI 28.5 ± 1.7 kg/m2 Repeated daily dose for 4 wk Sucralose ADA diet: components of diet not mentioned Modified diet: fructose and sucralose were used as sweeteners in a ratio of 30 to 70 Low-calorie diet: included fat-free bread with 8% fat replacer with β-glucans and oats, and cookies prepared with 50% fat replacer with β-glucans. Bread was consumed twice daily (60 g) each bread and 3 cookies (20 g/cookie) Significant improvement in HbA1c, lipid profile, and BMI, but not in fasting blood glucose, in both groups. Sucralose-containing diet resulted in greater improvement than the ADA diet, with a greater decrease in HbA1c Ma et al (2009)51 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 7; mean BMI 21.6 ± 1.2 kg/m2; mean age 24 ± 2 y Single dose on 4 occasions Sucralose All participants received intragastric infusion labeled with 150 mg of 13C-acetate: 500 mL of saline, 50 g of sucrose (positive control), 80 mg of sucralose, or 800 mg of sucralose Sucralose, when consumed alone, had no effect on blood glucose, insulin, plasma GLP-1, or GIP levels Brown et al (2009)52 Randomized crossover trial Healthy individuals; M and F; n = 22; mean BMI 25.6 ± 4.6 kg/m2; age 12–25 y Single dose, administered postprandially (OGTT) Sucralose Participants fasted before treatment and then ingested either 240 mL of carbonated water or 240 mL of diet drink containing sucralose (unknown concentration) and acesulfame K. Ten minutes after treatment, OGTT with 75 g of glucose was performed No effect of sucralose on glucose, insulin, GLP-1, or C-peptides following OGTT. GLP-1 peak (P = 0.003) and AUC (P = 0.003) were significantly higher with diet soda than with carbonated water Ma et al (2010)53 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; mean BMI 23.4 ± 0.8 kg/m2; mean age 27 ± 2 y Single dose on 2 occasions Sucralose Participants received intraduodenal infusion of either sucralose (960 mg) in saline or saline only for 150 min Sucralose infusion did not affect glucose or GLP-1 Brown et al (2011)54 Randomized crossover trial Healthy individuals; n = 8; F; mean BMI 22.1 ± 1.7 kg/m2; mean age 21.8 ± 2.5 y Single dose on 4 occasions, administered in fasting state and postprandially Sucralose Participants fasted before receiving treatment of 355 mL of water, 50 g of sucrose in 355 mL of water, 6 g of Splenda in 355 mL of water, or 50 g of sucrose and 6 g Splenda in 355 mL of water. Breakfast was given 1 h after treatment Sucralose, compared with water, had no significant effect on insulin, glucose, or glucagon levels Steinert et al (2011)55 Randomized, placebo-controlled, double-blinded, crossover trial Healthy individuals; n = 12; M and F; mean BMI 23 ± 0.5 kg/m2; mean age 23.3 ± 0.7 y Single dose on 6 occasions Sucralose, aspartame, acesulfame K Participants fasted before intragastric infusion of glucose (50 g in water), fructose (25 g in water), sucralose (62 mg in water), aspartame (169 mg in water), acesulfame K (220 mg in water), or control (250 mL of water) Sucralose, compared with water, had no significant effect on glucose, insulin, GLP-1, or appetite hormone response Ford et al (2011)56 Randomized, placebo-controlled, single-blinded, crossover trial Healthy individuals; M and F; n = 8; BMI 18.8–23.9 kg/m2; age 22–27 y Single dose on 3 occasions Sucralose Participants fasted before receiving treatment with 50 mL of water, 50 mL of sucralose (0.083% wt/vol), or 50 mL of sucralose (0.083% wt/vol) and maltodextrin (50% wt/vol), followed by modified sham-feeding protocol of same solution that was consumed to stimulate oral sweet receptors Consumption of sucralose or water, followed by modified sham feeding combined with sucralose, had no effect on plasma glucose, insulin, or GLP-1 concentrations. Consumption of sucralose with maltodextrin caused an increase in plasma glucose and insulin AUC without affecting GLP-1 Wu et al (2012)57 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 10; mean BMI 25.5 ± 1.5 kg/m2; mean age 28.8 ± 4.0 y Single dose on 4 occasions Sucralose Participants fasted before drinking preload drinks containing 40 g of glucose, 60 mg of sucralose, 40 g of 3-O-methylglucose, or 40 g of tagatose/isomalt mixture 15 min before consuming a labeled mashed potato meal containing 13C octanoic acid Sucralose had no effect on plasma blood glucose, GLP-1, GIP, or insulin Brown et al (2012)41 Randomized crossover trial 3 groups; M; age 13–24 y: Healthy participants: n = 25 Patients with T1DM: n = 9; mean BMI 21.7 ± 2.4 kg/m2 Obese patients with T2DM: n = 10; mean BMI 35.0 ± 6.8 kg/m2 Single dose on 2 occasions, administered postprandially (OGTT) Sucralose Participants fasted before consuming diet soda or carbonated water, Afterward, they consumed 240 mL of diet soda containing sucralose (190 ± 38 mg/mL) and acesulfame K (108 ± 0.6 mg/mL) or 240 mL of carbonated water as placeboOGTT with a 75-g glucose load was performed h after test drink was consumed T1DM individuals: GLP-1 AUC was 43% higher after diet soda consumption (P = 0.02)Healthy individuals: GLP-1 AUC was 34% higher after diet soda consumption (P = 0.029)All individuals: diet soda had no effect on glucose, C-peptides, or GIP Pepino et al (2013)44 Randomized crossover trial Morbidly obese individuals; M and F; n = 17; mean age 35.1 ± 1.0 y; mean BMI 41.0 ± 1.5 kg/m2; low consumption of NNSs (< 1 can of diet soda or < 1 spoonful of NNS per week) Single dose on 2 occasions, administered postprandially (OGTT) Sucralose After fasting, participants consumed either 60 mL of distilled water (control condition) or 60 mL of sucralose solution (2 mmol/L; 48 mg sucralose). OGTT with a 75-g glucose load was performed after treatment Glucose, insulin, and C-peptides were higher in sucralose group than in water group (P<0.004). Insulin sensitivity and insulin clearance both decreased: 23 ± 20% (P = 0.01) and 7 ± 4% (P = 0.04), respectively. No differences in GLP-1, GIP, or glucagon concentrations Wu et al (2013)58 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; M; mean BMI 25.5 ± 1.0 kg/m2; 33.6 ± 5.9 y Single dose on 4 occasions, administered in fasting state and postprandially (OGTT) Sucralose, acesulfame K Participants consumed either 240 mL of water alone or a similar amount of water sweetened with 52 mg of sucralose, 200 mg of acesulfame K, or 46 mg of sucralose and 26 mg of acesulfame K after an overnight fast. OGTT with 75 g of glucose and 150 mg of 13C-acetate was administered 10 min after each treatment Prior to glucose ingestion, blood glucose, plasma insulin, and GLP-1 levels remained unchanged after consumption of any of the sweetened drinks or water. Blood glucose, plasma insulin, and GLP-1 all increased after OGTT (P<0.001 for each) and were similar in all treatment groups Stellingwerff et al (2013)59 Randomized, double-blinded, crossover trial Healthy individuals; M; n = 23; mean BMI 23.1 ± 1.9 kg/m2; mean age 29 ± 7 y Single dose, given before, during, and after 2 h of exercise (cycling) Sucralose Eight 50-mL doses of either 1mM (20 mg) sucralose solution or placebo (sucralose mouthwash followed by drinking 50 mL of water) every 15 min for 2 h, starting 120 min prior to beginning of exercise Sucralose had no effect on blood glucose or insulin levels Temizkan et al (2015)60 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 8; mean age 45.0 ± 4.1 y; mean BMI 30.3 ± 4.5 kg/m2 Patients with newly diagnosed T2DM; M and F; n = 8; mean age 51.5 ± 9.2 y; mean BMI 33.7 ± 5.4 kg/m2 Single dose on 3 occasions, administered postprandially (OGTT) Sucralose, aspartame Participants consumed 24 mg of sucralose (tabletop formulation) in 200 mL of water or 72 mg of aspartame (tabletop formulation) in 200 mL of water or or 200 mL of water alone. OGTT (75 g of glucose) was performed 15 min after treatment Sucralose, compared with water, was associated with lower blood glucose AUC (P = 0.002) and increased GLP-1 AUC (P = 0.04) in healthy individuals No effect of sucralose on insulin or C-peptides levels No effect of sucralose on glucose, insulin, C-peptides, or GLP-1 in T2DM individuals Sylvetsky et al (2016)61 Randomized crossover trial Study arm 1: healthy individuals; n = 30; M and F; mean BMI 25.8 ± 4.2 kg/m2; mean age 29.7 ± 7.6 y Study arm 2: healthy individuals; n = 31; M and F; mean BMI 26.3 ± 7.5 kg/m2; mean age 27.4 ± 6.7 y Single dose, administered postprandially (OGTT) Sucralose, aspartame, acesulfame K Participants fasted before consuming beverages: Study arm 1: 355 mL of water alone; 355 mL of water plus sucralose (68 mg); 355 mL of water plus sucralose (170 mg); or 355 mL water plus sucralose (250 mg) Study arm 2: 355 mL of carbonated water alone; 355 mL of diet soda (18 mg sucralose + 18 mg acesulfame K + 57 mg aspartame + other ingredients); 355 mL of diet soda (68 mg sucralose + 41 mg acesulfame K + other ingredients); or 355 mL of carbonated water plus sucralose (68 mg) and acesulfame K (41 mg) Study arm 1: Sucralose preload of different doses had no effect on glucose, insulin, C-peptide, glucose absorption, or gut hormones GLP-1 and GIP. Carbonated water with NNSs, compared with carbonated water alone, also had no effect on the parameters measured Study arm 2: Sucralose preload with acesulfame K had no effect on metabolic outcomes. GLP-1 was increased after diet soda intake Grotz et al (2017)62 Randomized, double-blinded, parallel trial Healthy adults; n = 47; M; age 18–45 y; BMI 19.4–27.0 kg/m2 Repeated daily dose for 12 wk Sucralose Participants consumed capsules containing ≈ 333.3 mg of sucralose or placebo (cellulose), 3 times daily at mealtimes No differences between groups in change from baseline for fasting glucose, insulin, or HbA1c Romo-Romo et al (2018)63 Randomized, open-label, parallel-arm trial Healthy adults; n = 66; F; age 18–55 y; BMI 18.5–24.9 kg/m2; low consumers of NNSs (< 5 portions per week, regardless of product type) Repeated daily dose for 14 d Sucralose Participants consumed 1 commercial packet 3 times daily (12 mg sucralose, 958 mg dextrose, and 30 mg maltodextrin) added to beverage or meals. Control group consumed similar treatment, without sucralose Sucralose group showed significant decrease in insulin sensitivity compared with control group (P = 0.04). Acute insulin response increased in sucralose group (P = 0.04) Lertrit et al (2018)42 Randomized, double-blinded, crossover trial Healthy adults; n = 15; M and F; age 18–59 y; BMI 18.5–27 kg/m2 Repeated daily dose for 4 wk, admininstered postprandially (OGTT) Sucralose Participants consumed capsules containing 200 mg of sucralose or placebo Acute insulin response and sensitivity decreased in sucralose group (P<0.005). AUC of active GLP-1 increased in sucralose group (P<0.001) Nehrling et al (1985)64 Randomized, double-blinded, placebo-controlled trial Patients with IDDM or NIDD; n = 62; age 18–65 y Repeated daily dose for 18 wk Aspartame Participants consumed aspartame capsules (2.7 g) or placebo capsules (20 mg corn starch), daily with meals After treatment, blood glucose and HbA1c levels were similar in both groups Horwitz et al (1988)65 Randomized crossover trial Healthy individuals; F; n = 12; mean. age 28 ± 8 y; mean BMI 22.5 kg/m2 Patients with NIDDM on oral hypglycemic agents; F; n = 10; mean age 57 ± 8 y; mean BMI 33.7 kg/m2 Single dose on 3 occasions Aspartame, saccharin After an overnight fast, participants consumed 400 mg of aspartame and 300 mL of cherry-flavored Kool-Aid or 135 mg of saccharin and 300 mL of cherry-flavored Kool-Aid No significant changes in plasma glucose, insulin, or glucagon levels in any treatment group. In healthy participants, mean AUC insulin concentration was higher after aspartame consumption than after saccharin or control beverage consumption (P<0.05) Colagiuri et al (1989)66 Controlled, double-blinded, crossover trial NIDDM; M and F; n = 9; mean age 66 ± 5 y; mean BMI 26.4 ± 2.1 kg/m2 Repeated daily dose for 6 wk Aspartame, sucrose Participants consumed 45 g of sucrose and 162 mg of aspartame, added to meals and beverages daily Aspartame consumption did not cause changes in glucose and HbA1c levels Rodin (1990)67 Randomized crossover trial Overweight and normal-weight healthy individuals; n = 24; age 22–50 y Single dose Aspartame Participants consumed aspartame (250 mg) or fructose (50 g) or glucose (50 g) in 500 mL of water, or water alone as control No significant effects of aspartame on glucose, insulin, or glucagon levels Moller (1991)45 Randomized trial Healthy individuals; n = 6; M; age 22–37 y; weight 63–83 kg Single dose Aspartame Participants consumed aspartame (1 g) or bovine albumin (12.2 g) in 200 mL of water, or water alone as a control Aspartame, compared with control, resulted in decreased glucose concentrations (P<0.05). Insulin levels were not affected in any of the 3 groups Härtel et al (1993)68 Randomized clinical trial Healthy individuals; M and F; n = 14; age 19–52 y Single dose Aspartame, acesulfame K, saccharin Participants consumed 330 mL of water containing aspartame (165 mg), sucrose (33 g), acesulfame K (165 mg), cyclamate (800 mg), or saccharin (75 mg) NNS consumption, compared with sucrose consumption, had no effect on insulin or glucose concentrations Melanson et al (1999)46 Randomized, crossover trial Healthy individuals; n = 10; age 19–31 y; mean BMI 23.4 ± 1.9 kg/m2 Single dose Aspartame Participants consumed drinks containing aspartame, high fat, or carbohydrate, followed by ad libitum meals Blood glucose concentration decreased (P = 0.014) in 40% of participants after aspartame consumption Hall et al (2003)43 Crossover trial Healthy individuals; n = 6; age 24–31 y; BMI < 25 kg/m2 Single dose on 3 occasions Aspartame Participants consumed capsules containg aspartame (400 mg) or aspartic acid (176 mg) plus phenylalanine (224 mg) or control (400 mg of corn flour) Consumption of aspartame and amino acids resulted in decreased plasma GLP-1 (P<0.05). Aspartame did not affect glucose, insulin, or GIP concentrations Anton et al (2013)69 Crossover trial Healthy lean individuals; M and F; n = 19; age 18–50 y; BMI 20.0–24.9 kg/m2 Obese individuals; M and F; n = 12; age 18–50 y; BMI 30.0–39.9 kg/m2 Single dose on 3 occasions Aspartame, stevia, sucrose Participants consumed tea sweetened with aspartame or stevia or sucrose before they consumed a buffet-type meal ad libitum. Quantities were specified in kilocalories only, not milligrams Stevia, compared with sucrose, lowered plasma glucose and insulin levels (P<0.01 and P<0.05, respectively) Maersk et al (2012)70 Open crossover trial Healthy obese individuals; n = 24; mean age 33.5 ± 9.2 y; mean BMI 31.4 ± 3.11 kg/m2 Single dose on 4 occasions Aspartame Participants consumed 500 mL of a regular cola drink (sweetened with sucrose) or 500 mL of skimmed milk or 500 mL of a diet cola drink (sweetened with aspartame) or 500 mL of water Diet cola drink (sweetened with aspartame) had no effect on glucose, insulin, GLP-1, GIP, or ghrelin levels Olalde-Mendoza & Moreno-González (2013)71 Randomized trial Patients with T2DM on medication; n = 80; mean age 49.3 ± 9.0 y; mean BMI 30.5 ± 4.3 kg/m2 Single dose Aspartame, acesulfame K, regular (sugared) soda Participants consumed test beverage after an overnight fast: Group 1: 200 mL of of diet soda (containing 40 mg aspartame + 100 g acesulfame K) Group 2: 200 mL of regular soda (sweetened with sucrose) No effect of diet soda on capillary blood glucose levels Bryant et al (2014)72 Randomized crossover trial Healthy individuals; M and F; n = 10; age 18–24 y; mean BMI 21.8 ± 1.8 kg/m2 Single dose on 4 occasions Aspartame, saccharin, acesulfame K After an overnight fast, participants consumed a beverage containing the following in 250 mL of water: 45 g of glucose; 45 g of glucose and 150 mg of aspartame; 45 g of glucose and 85 mg of acesulfame K; or 45 g of glucose and 20 mg of saccharin NNS consumption had no effect on glucose concentrations Tey et al (2017)73 Randomized, double-blinded, crossover trial Healthy individuals; n = 30; M; age 21–50 y; BMI 18.5–25.0 kg/m2 Single dose on 1 occasions Aspartame, monk fruit extract, stevia, sucrose Participants consumed beverages given as preload containing the following: 0.44 g of aspartame and 500 mL of water; 0.63 g of monk fruit extract (50% mogroside) and 500 mL of water; 0.33 g of stevia (containing rebaudioside A, a steviol glycoside) and 500 mL of water; or 65 g of sucrose and 500 mL of water. Beverages were consumed 1 h before ad libitum lunch No effect of any treatment on glucose AUC or insulin AUC Higgins et al (2018)74 Randomized parallel-arm trial Healthy individuals; n = 93; M and F; age 18–60 y; BMI 18–25 kg/m2; not consumers of NNSs Repeated daily dose for 12 wk Aspartame Three groups of participants: Group that received no aspartame: took 2 capsules containing a total of 680 mg of dextrose and 80 mg of PABA plus 2 empty capsules Group that received 350 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 2 capsules containing a total of 680 mg of dextrose plus 2 empty capsules Group that received 1050 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 4 capsules containing a total of 700 mg of aspartame and 680 mg of dextrose No significant difference between groups in glucose, insulin, GLP-1, or GIP at baseline or week 12 Bonnet et al (2018)75 Randomized, double-blinded, crossover trial Healthy individuals; n = 50; M; mean age 31.1 ± 10.3 y; BMI 19–29 kg/m2; not regular consumers of NNSs (<1 can of beverage with high-intensity sweeteners per week) Repeated daily dose for 12 wk Aspartame, acesulfame K Participants consumed 330 mL of beverage containing 129 mg of aspartame and 13 mg of acesulfame K in carbonated water twice daily. Control group received 330 mL of carbonated water twice daily No significant difference between groups in insulin sensitivity or secretion Reference . Study design . Population characteristics . Duration of intervention . Type of NNS used . Dose of NNS used and method of administration . Main outcomes . Mezitis et al (1996)47 Randomized crossover trial Patients with T1DM or T2DM; M and F; n = 26; age < 65 y Single dose Sucralose Participants received sucralose (1000-mg capsule) or placebo (cellulose capsule), followed by a meal Sucralose consumption, compared with placebo, had no effect on glucose or C-peptide levels Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F Study 1: n = 8; mean age 32 y; mean weight 70 kg Repeated daily dose for 17 d Sucralose Participants fasted before the intervention. Sucralose supplied in aqueous solution (5 mg/mL) Phase 1: day 1: 0 mg/kg/d; day 3: 1.0 mg/kg/d; day 5: 2.5 mg/kg/d; day 7: 5 mg/kg/d; day 9: 10.0 mg/kg/d. Phase 2: day 11–13: 2.0 mg/kg/d; day 14–17: 5.0 mg/kg/d; day 18–25: 0 mg/kg/d No effect on fasting glucose or insulin Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F, mean weight 71.5 kg Study 2, sucralose group: n = 77; mean age 34.6 y Study 2, control group: n = 31; mean age 33.9 y Repeated daily dose for 13 wk Sucralose Sucralose supplied in aqueous solution (5 mg/mL) and consumed twice daily for a total daily dose: Sucralose group: weeks 1–3: 125 mg/d; weeks 4–7: 250 mg/d, weeks 5–12: 500 mg/d Control group (fructose): weeks 1–13: 50 g/d No effect on fasting glucose or insulin Grotz et al (2003)49 Randomized, double-blinded, placebo-controlled trial Obese adults with T2DM; M and F; N = 136; age 31–70 y; mean BMI 31.6 kg/m2 Sucralose group: n = 67 Placebo group: n = 69 Repeated daily dose for 13 wk Follow-up: 4 wk Sucralose Sucralose group: 1 capsule containing sucralose (333.5 mg) supplied twice daily. Total daily intake was 667 mg Placebo group: 1 capsule containing cellulose, supplied twice daily Follow-up phase: 1 cellulose capsules, supplied daily No significant differences in plasma glucose, insulin, serum C-peptides, or HbA1c levels between sucralose and placebo groups over the entire study period Reyna et al (2003)50 Randomized, controlled clinical trial Adults with T2DM; M; mean age 45 ± 55 y Control group (ADA diet): n = 8; mean BMI 28.9 ± 2.0 kg/m2 Expermintal group (modified ADA diet): n = 8; mean BMI 28.5 ± 1.7 kg/m2 Repeated daily dose for 4 wk Sucralose ADA diet: components of diet not mentioned Modified diet: fructose and sucralose were used as sweeteners in a ratio of 30 to 70 Low-calorie diet: included fat-free bread with 8% fat replacer with β-glucans and oats, and cookies prepared with 50% fat replacer with β-glucans. Bread was consumed twice daily (60 g) each bread and 3 cookies (20 g/cookie) Significant improvement in HbA1c, lipid profile, and BMI, but not in fasting blood glucose, in both groups. Sucralose-containing diet resulted in greater improvement than the ADA diet, with a greater decrease in HbA1c Ma et al (2009)51 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 7; mean BMI 21.6 ± 1.2 kg/m2; mean age 24 ± 2 y Single dose on 4 occasions Sucralose All participants received intragastric infusion labeled with 150 mg of 13C-acetate: 500 mL of saline, 50 g of sucrose (positive control), 80 mg of sucralose, or 800 mg of sucralose Sucralose, when consumed alone, had no effect on blood glucose, insulin, plasma GLP-1, or GIP levels Brown et al (2009)52 Randomized crossover trial Healthy individuals; M and F; n = 22; mean BMI 25.6 ± 4.6 kg/m2; age 12–25 y Single dose, administered postprandially (OGTT) Sucralose Participants fasted before treatment and then ingested either 240 mL of carbonated water or 240 mL of diet drink containing sucralose (unknown concentration) and acesulfame K. Ten minutes after treatment, OGTT with 75 g of glucose was performed No effect of sucralose on glucose, insulin, GLP-1, or C-peptides following OGTT. GLP-1 peak (P = 0.003) and AUC (P = 0.003) were significantly higher with diet soda than with carbonated water Ma et al (2010)53 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; mean BMI 23.4 ± 0.8 kg/m2; mean age 27 ± 2 y Single dose on 2 occasions Sucralose Participants received intraduodenal infusion of either sucralose (960 mg) in saline or saline only for 150 min Sucralose infusion did not affect glucose or GLP-1 Brown et al (2011)54 Randomized crossover trial Healthy individuals; n = 8; F; mean BMI 22.1 ± 1.7 kg/m2; mean age 21.8 ± 2.5 y Single dose on 4 occasions, administered in fasting state and postprandially Sucralose Participants fasted before receiving treatment of 355 mL of water, 50 g of sucrose in 355 mL of water, 6 g of Splenda in 355 mL of water, or 50 g of sucrose and 6 g Splenda in 355 mL of water. Breakfast was given 1 h after treatment Sucralose, compared with water, had no significant effect on insulin, glucose, or glucagon levels Steinert et al (2011)55 Randomized, placebo-controlled, double-blinded, crossover trial Healthy individuals; n = 12; M and F; mean BMI 23 ± 0.5 kg/m2; mean age 23.3 ± 0.7 y Single dose on 6 occasions Sucralose, aspartame, acesulfame K Participants fasted before intragastric infusion of glucose (50 g in water), fructose (25 g in water), sucralose (62 mg in water), aspartame (169 mg in water), acesulfame K (220 mg in water), or control (250 mL of water) Sucralose, compared with water, had no significant effect on glucose, insulin, GLP-1, or appetite hormone response Ford et al (2011)56 Randomized, placebo-controlled, single-blinded, crossover trial Healthy individuals; M and F; n = 8; BMI 18.8–23.9 kg/m2; age 22–27 y Single dose on 3 occasions Sucralose Participants fasted before receiving treatment with 50 mL of water, 50 mL of sucralose (0.083% wt/vol), or 50 mL of sucralose (0.083% wt/vol) and maltodextrin (50% wt/vol), followed by modified sham-feeding protocol of same solution that was consumed to stimulate oral sweet receptors Consumption of sucralose or water, followed by modified sham feeding combined with sucralose, had no effect on plasma glucose, insulin, or GLP-1 concentrations. Consumption of sucralose with maltodextrin caused an increase in plasma glucose and insulin AUC without affecting GLP-1 Wu et al (2012)57 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 10; mean BMI 25.5 ± 1.5 kg/m2; mean age 28.8 ± 4.0 y Single dose on 4 occasions Sucralose Participants fasted before drinking preload drinks containing 40 g of glucose, 60 mg of sucralose, 40 g of 3-O-methylglucose, or 40 g of tagatose/isomalt mixture 15 min before consuming a labeled mashed potato meal containing 13C octanoic acid Sucralose had no effect on plasma blood glucose, GLP-1, GIP, or insulin Brown et al (2012)41 Randomized crossover trial 3 groups; M; age 13–24 y: Healthy participants: n = 25 Patients with T1DM: n = 9; mean BMI 21.7 ± 2.4 kg/m2 Obese patients with T2DM: n = 10; mean BMI 35.0 ± 6.8 kg/m2 Single dose on 2 occasions, administered postprandially (OGTT) Sucralose Participants fasted before consuming diet soda or carbonated water, Afterward, they consumed 240 mL of diet soda containing sucralose (190 ± 38 mg/mL) and acesulfame K (108 ± 0.6 mg/mL) or 240 mL of carbonated water as placeboOGTT with a 75-g glucose load was performed h after test drink was consumed T1DM individuals: GLP-1 AUC was 43% higher after diet soda consumption (P = 0.02)Healthy individuals: GLP-1 AUC was 34% higher after diet soda consumption (P = 0.029)All individuals: diet soda had no effect on glucose, C-peptides, or GIP Pepino et al (2013)44 Randomized crossover trial Morbidly obese individuals; M and F; n = 17; mean age 35.1 ± 1.0 y; mean BMI 41.0 ± 1.5 kg/m2; low consumption of NNSs (< 1 can of diet soda or < 1 spoonful of NNS per week) Single dose on 2 occasions, administered postprandially (OGTT) Sucralose After fasting, participants consumed either 60 mL of distilled water (control condition) or 60 mL of sucralose solution (2 mmol/L; 48 mg sucralose). OGTT with a 75-g glucose load was performed after treatment Glucose, insulin, and C-peptides were higher in sucralose group than in water group (P<0.004). Insulin sensitivity and insulin clearance both decreased: 23 ± 20% (P = 0.01) and 7 ± 4% (P = 0.04), respectively. No differences in GLP-1, GIP, or glucagon concentrations Wu et al (2013)58 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; M; mean BMI 25.5 ± 1.0 kg/m2; 33.6 ± 5.9 y Single dose on 4 occasions, administered in fasting state and postprandially (OGTT) Sucralose, acesulfame K Participants consumed either 240 mL of water alone or a similar amount of water sweetened with 52 mg of sucralose, 200 mg of acesulfame K, or 46 mg of sucralose and 26 mg of acesulfame K after an overnight fast. OGTT with 75 g of glucose and 150 mg of 13C-acetate was administered 10 min after each treatment Prior to glucose ingestion, blood glucose, plasma insulin, and GLP-1 levels remained unchanged after consumption of any of the sweetened drinks or water. Blood glucose, plasma insulin, and GLP-1 all increased after OGTT (P<0.001 for each) and were similar in all treatment groups Stellingwerff et al (2013)59 Randomized, double-blinded, crossover trial Healthy individuals; M; n = 23; mean BMI 23.1 ± 1.9 kg/m2; mean age 29 ± 7 y Single dose, given before, during, and after 2 h of exercise (cycling) Sucralose Eight 50-mL doses of either 1mM (20 mg) sucralose solution or placebo (sucralose mouthwash followed by drinking 50 mL of water) every 15 min for 2 h, starting 120 min prior to beginning of exercise Sucralose had no effect on blood glucose or insulin levels Temizkan et al (2015)60 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 8; mean age 45.0 ± 4.1 y; mean BMI 30.3 ± 4.5 kg/m2 Patients with newly diagnosed T2DM; M and F; n = 8; mean age 51.5 ± 9.2 y; mean BMI 33.7 ± 5.4 kg/m2 Single dose on 3 occasions, administered postprandially (OGTT) Sucralose, aspartame Participants consumed 24 mg of sucralose (tabletop formulation) in 200 mL of water or 72 mg of aspartame (tabletop formulation) in 200 mL of water or or 200 mL of water alone. OGTT (75 g of glucose) was performed 15 min after treatment Sucralose, compared with water, was associated with lower blood glucose AUC (P = 0.002) and increased GLP-1 AUC (P = 0.04) in healthy individuals No effect of sucralose on insulin or C-peptides levels No effect of sucralose on glucose, insulin, C-peptides, or GLP-1 in T2DM individuals Sylvetsky et al (2016)61 Randomized crossover trial Study arm 1: healthy individuals; n = 30; M and F; mean BMI 25.8 ± 4.2 kg/m2; mean age 29.7 ± 7.6 y Study arm 2: healthy individuals; n = 31; M and F; mean BMI 26.3 ± 7.5 kg/m2; mean age 27.4 ± 6.7 y Single dose, administered postprandially (OGTT) Sucralose, aspartame, acesulfame K Participants fasted before consuming beverages: Study arm 1: 355 mL of water alone; 355 mL of water plus sucralose (68 mg); 355 mL of water plus sucralose (170 mg); or 355 mL water plus sucralose (250 mg) Study arm 2: 355 mL of carbonated water alone; 355 mL of diet soda (18 mg sucralose + 18 mg acesulfame K + 57 mg aspartame + other ingredients); 355 mL of diet soda (68 mg sucralose + 41 mg acesulfame K + other ingredients); or 355 mL of carbonated water plus sucralose (68 mg) and acesulfame K (41 mg) Study arm 1: Sucralose preload of different doses had no effect on glucose, insulin, C-peptide, glucose absorption, or gut hormones GLP-1 and GIP. Carbonated water with NNSs, compared with carbonated water alone, also had no effect on the parameters measured Study arm 2: Sucralose preload with acesulfame K had no effect on metabolic outcomes. GLP-1 was increased after diet soda intake Grotz et al (2017)62 Randomized, double-blinded, parallel trial Healthy adults; n = 47; M; age 18–45 y; BMI 19.4–27.0 kg/m2 Repeated daily dose for 12 wk Sucralose Participants consumed capsules containing ≈ 333.3 mg of sucralose or placebo (cellulose), 3 times daily at mealtimes No differences between groups in change from baseline for fasting glucose, insulin, or HbA1c Romo-Romo et al (2018)63 Randomized, open-label, parallel-arm trial Healthy adults; n = 66; F; age 18–55 y; BMI 18.5–24.9 kg/m2; low consumers of NNSs (< 5 portions per week, regardless of product type) Repeated daily dose for 14 d Sucralose Participants consumed 1 commercial packet 3 times daily (12 mg sucralose, 958 mg dextrose, and 30 mg maltodextrin) added to beverage or meals. Control group consumed similar treatment, without sucralose Sucralose group showed significant decrease in insulin sensitivity compared with control group (P = 0.04). Acute insulin response increased in sucralose group (P = 0.04) Lertrit et al (2018)42 Randomized, double-blinded, crossover trial Healthy adults; n = 15; M and F; age 18–59 y; BMI 18.5–27 kg/m2 Repeated daily dose for 4 wk, admininstered postprandially (OGTT) Sucralose Participants consumed capsules containing 200 mg of sucralose or placebo Acute insulin response and sensitivity decreased in sucralose group (P<0.005). AUC of active GLP-1 increased in sucralose group (P<0.001) Nehrling et al (1985)64 Randomized, double-blinded, placebo-controlled trial Patients with IDDM or NIDD; n = 62; age 18–65 y Repeated daily dose for 18 wk Aspartame Participants consumed aspartame capsules (2.7 g) or placebo capsules (20 mg corn starch), daily with meals After treatment, blood glucose and HbA1c levels were similar in both groups Horwitz et al (1988)65 Randomized crossover trial Healthy individuals; F; n = 12; mean. age 28 ± 8 y; mean BMI 22.5 kg/m2 Patients with NIDDM on oral hypglycemic agents; F; n = 10; mean age 57 ± 8 y; mean BMI 33.7 kg/m2 Single dose on 3 occasions Aspartame, saccharin After an overnight fast, participants consumed 400 mg of aspartame and 300 mL of cherry-flavored Kool-Aid or 135 mg of saccharin and 300 mL of cherry-flavored Kool-Aid No significant changes in plasma glucose, insulin, or glucagon levels in any treatment group. In healthy participants, mean AUC insulin concentration was higher after aspartame consumption than after saccharin or control beverage consumption (P<0.05) Colagiuri et al (1989)66 Controlled, double-blinded, crossover trial NIDDM; M and F; n = 9; mean age 66 ± 5 y; mean BMI 26.4 ± 2.1 kg/m2 Repeated daily dose for 6 wk Aspartame, sucrose Participants consumed 45 g of sucrose and 162 mg of aspartame, added to meals and beverages daily Aspartame consumption did not cause changes in glucose and HbA1c levels Rodin (1990)67 Randomized crossover trial Overweight and normal-weight healthy individuals; n = 24; age 22–50 y Single dose Aspartame Participants consumed aspartame (250 mg) or fructose (50 g) or glucose (50 g) in 500 mL of water, or water alone as control No significant effects of aspartame on glucose, insulin, or glucagon levels Moller (1991)45 Randomized trial Healthy individuals; n = 6; M; age 22–37 y; weight 63–83 kg Single dose Aspartame Participants consumed aspartame (1 g) or bovine albumin (12.2 g) in 200 mL of water, or water alone as a control Aspartame, compared with control, resulted in decreased glucose concentrations (P<0.05). Insulin levels were not affected in any of the 3 groups Härtel et al (1993)68 Randomized clinical trial Healthy individuals; M and F; n = 14; age 19–52 y Single dose Aspartame, acesulfame K, saccharin Participants consumed 330 mL of water containing aspartame (165 mg), sucrose (33 g), acesulfame K (165 mg), cyclamate (800 mg), or saccharin (75 mg) NNS consumption, compared with sucrose consumption, had no effect on insulin or glucose concentrations Melanson et al (1999)46 Randomized, crossover trial Healthy individuals; n = 10; age 19–31 y; mean BMI 23.4 ± 1.9 kg/m2 Single dose Aspartame Participants consumed drinks containing aspartame, high fat, or carbohydrate, followed by ad libitum meals Blood glucose concentration decreased (P = 0.014) in 40% of participants after aspartame consumption Hall et al (2003)43 Crossover trial Healthy individuals; n = 6; age 24–31 y; BMI < 25 kg/m2 Single dose on 3 occasions Aspartame Participants consumed capsules containg aspartame (400 mg) or aspartic acid (176 mg) plus phenylalanine (224 mg) or control (400 mg of corn flour) Consumption of aspartame and amino acids resulted in decreased plasma GLP-1 (P<0.05). Aspartame did not affect glucose, insulin, or GIP concentrations Anton et al (2013)69 Crossover trial Healthy lean individuals; M and F; n = 19; age 18–50 y; BMI 20.0–24.9 kg/m2 Obese individuals; M and F; n = 12; age 18–50 y; BMI 30.0–39.9 kg/m2 Single dose on 3 occasions Aspartame, stevia, sucrose Participants consumed tea sweetened with aspartame or stevia or sucrose before they consumed a buffet-type meal ad libitum. Quantities were specified in kilocalories only, not milligrams Stevia, compared with sucrose, lowered plasma glucose and insulin levels (P<0.01 and P<0.05, respectively) Maersk et al (2012)70 Open crossover trial Healthy obese individuals; n = 24; mean age 33.5 ± 9.2 y; mean BMI 31.4 ± 3.11 kg/m2 Single dose on 4 occasions Aspartame Participants consumed 500 mL of a regular cola drink (sweetened with sucrose) or 500 mL of skimmed milk or 500 mL of a diet cola drink (sweetened with aspartame) or 500 mL of water Diet cola drink (sweetened with aspartame) had no effect on glucose, insulin, GLP-1, GIP, or ghrelin levels Olalde-Mendoza & Moreno-González (2013)71 Randomized trial Patients with T2DM on medication; n = 80; mean age 49.3 ± 9.0 y; mean BMI 30.5 ± 4.3 kg/m2 Single dose Aspartame, acesulfame K, regular (sugared) soda Participants consumed test beverage after an overnight fast: Group 1: 200 mL of of diet soda (containing 40 mg aspartame + 100 g acesulfame K) Group 2: 200 mL of regular soda (sweetened with sucrose) No effect of diet soda on capillary blood glucose levels Bryant et al (2014)72 Randomized crossover trial Healthy individuals; M and F; n = 10; age 18–24 y; mean BMI 21.8 ± 1.8 kg/m2 Single dose on 4 occasions Aspartame, saccharin, acesulfame K After an overnight fast, participants consumed a beverage containing the following in 250 mL of water: 45 g of glucose; 45 g of glucose and 150 mg of aspartame; 45 g of glucose and 85 mg of acesulfame K; or 45 g of glucose and 20 mg of saccharin NNS consumption had no effect on glucose concentrations Tey et al (2017)73 Randomized, double-blinded, crossover trial Healthy individuals; n = 30; M; age 21–50 y; BMI 18.5–25.0 kg/m2 Single dose on 1 occasions Aspartame, monk fruit extract, stevia, sucrose Participants consumed beverages given as preload containing the following: 0.44 g of aspartame and 500 mL of water; 0.63 g of monk fruit extract (50% mogroside) and 500 mL of water; 0.33 g of stevia (containing rebaudioside A, a steviol glycoside) and 500 mL of water; or 65 g of sucrose and 500 mL of water. Beverages were consumed 1 h before ad libitum lunch No effect of any treatment on glucose AUC or insulin AUC Higgins et al (2018)74 Randomized parallel-arm trial Healthy individuals; n = 93; M and F; age 18–60 y; BMI 18–25 kg/m2; not consumers of NNSs Repeated daily dose for 12 wk Aspartame Three groups of participants: Group that received no aspartame: took 2 capsules containing a total of 680 mg of dextrose and 80 mg of PABA plus 2 empty capsules Group that received 350 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 2 capsules containing a total of 680 mg of dextrose plus 2 empty capsules Group that received 1050 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 4 capsules containing a total of 700 mg of aspartame and 680 mg of dextrose No significant difference between groups in glucose, insulin, GLP-1, or GIP at baseline or week 12 Bonnet et al (2018)75 Randomized, double-blinded, crossover trial Healthy individuals; n = 50; M; mean age 31.1 ± 10.3 y; BMI 19–29 kg/m2; not regular consumers of NNSs (<1 can of beverage with high-intensity sweeteners per week) Repeated daily dose for 12 wk Aspartame, acesulfame K Participants consumed 330 mL of beverage containing 129 mg of aspartame and 13 mg of acesulfame K in carbonated water twice daily. Control group received 330 mL of carbonated water twice daily No significant difference between groups in insulin sensitivity or secretion Abbreviations: acesulfame K; acesulfame potassium; ADA, American Diabetes Association; AUC, area under the curve; BMI, body mass index; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; HbA1c, hemoglobin A1c; IDDM, insulin-dependent diabetes mellitus; NIDD, non-insulin-dependent diabetes; NIDDM, non-insulin-dependent diabetes mellitus; OGTT, oral glucose tolerance test; PABA, para-amino benzoic acid; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. Open in new tab Table 2 Studies evaluating the effects of non-nutritive sweetener (NNS) consumption on glucose metabolism Reference . Study design . Population characteristics . Duration of intervention . Type of NNS used . Dose of NNS used and method of administration . Main outcomes . Mezitis et al (1996)47 Randomized crossover trial Patients with T1DM or T2DM; M and F; n = 26; age < 65 y Single dose Sucralose Participants received sucralose (1000-mg capsule) or placebo (cellulose capsule), followed by a meal Sucralose consumption, compared with placebo, had no effect on glucose or C-peptide levels Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F Study 1: n = 8; mean age 32 y; mean weight 70 kg Repeated daily dose for 17 d Sucralose Participants fasted before the intervention. Sucralose supplied in aqueous solution (5 mg/mL) Phase 1: day 1: 0 mg/kg/d; day 3: 1.0 mg/kg/d; day 5: 2.5 mg/kg/d; day 7: 5 mg/kg/d; day 9: 10.0 mg/kg/d. Phase 2: day 11–13: 2.0 mg/kg/d; day 14–17: 5.0 mg/kg/d; day 18–25: 0 mg/kg/d No effect on fasting glucose or insulin Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F, mean weight 71.5 kg Study 2, sucralose group: n = 77; mean age 34.6 y Study 2, control group: n = 31; mean age 33.9 y Repeated daily dose for 13 wk Sucralose Sucralose supplied in aqueous solution (5 mg/mL) and consumed twice daily for a total daily dose: Sucralose group: weeks 1–3: 125 mg/d; weeks 4–7: 250 mg/d, weeks 5–12: 500 mg/d Control group (fructose): weeks 1–13: 50 g/d No effect on fasting glucose or insulin Grotz et al (2003)49 Randomized, double-blinded, placebo-controlled trial Obese adults with T2DM; M and F; N = 136; age 31–70 y; mean BMI 31.6 kg/m2 Sucralose group: n = 67 Placebo group: n = 69 Repeated daily dose for 13 wk Follow-up: 4 wk Sucralose Sucralose group: 1 capsule containing sucralose (333.5 mg) supplied twice daily. Total daily intake was 667 mg Placebo group: 1 capsule containing cellulose, supplied twice daily Follow-up phase: 1 cellulose capsules, supplied daily No significant differences in plasma glucose, insulin, serum C-peptides, or HbA1c levels between sucralose and placebo groups over the entire study period Reyna et al (2003)50 Randomized, controlled clinical trial Adults with T2DM; M; mean age 45 ± 55 y Control group (ADA diet): n = 8; mean BMI 28.9 ± 2.0 kg/m2 Expermintal group (modified ADA diet): n = 8; mean BMI 28.5 ± 1.7 kg/m2 Repeated daily dose for 4 wk Sucralose ADA diet: components of diet not mentioned Modified diet: fructose and sucralose were used as sweeteners in a ratio of 30 to 70 Low-calorie diet: included fat-free bread with 8% fat replacer with β-glucans and oats, and cookies prepared with 50% fat replacer with β-glucans. Bread was consumed twice daily (60 g) each bread and 3 cookies (20 g/cookie) Significant improvement in HbA1c, lipid profile, and BMI, but not in fasting blood glucose, in both groups. Sucralose-containing diet resulted in greater improvement than the ADA diet, with a greater decrease in HbA1c Ma et al (2009)51 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 7; mean BMI 21.6 ± 1.2 kg/m2; mean age 24 ± 2 y Single dose on 4 occasions Sucralose All participants received intragastric infusion labeled with 150 mg of 13C-acetate: 500 mL of saline, 50 g of sucrose (positive control), 80 mg of sucralose, or 800 mg of sucralose Sucralose, when consumed alone, had no effect on blood glucose, insulin, plasma GLP-1, or GIP levels Brown et al (2009)52 Randomized crossover trial Healthy individuals; M and F; n = 22; mean BMI 25.6 ± 4.6 kg/m2; age 12–25 y Single dose, administered postprandially (OGTT) Sucralose Participants fasted before treatment and then ingested either 240 mL of carbonated water or 240 mL of diet drink containing sucralose (unknown concentration) and acesulfame K. Ten minutes after treatment, OGTT with 75 g of glucose was performed No effect of sucralose on glucose, insulin, GLP-1, or C-peptides following OGTT. GLP-1 peak (P = 0.003) and AUC (P = 0.003) were significantly higher with diet soda than with carbonated water Ma et al (2010)53 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; mean BMI 23.4 ± 0.8 kg/m2; mean age 27 ± 2 y Single dose on 2 occasions Sucralose Participants received intraduodenal infusion of either sucralose (960 mg) in saline or saline only for 150 min Sucralose infusion did not affect glucose or GLP-1 Brown et al (2011)54 Randomized crossover trial Healthy individuals; n = 8; F; mean BMI 22.1 ± 1.7 kg/m2; mean age 21.8 ± 2.5 y Single dose on 4 occasions, administered in fasting state and postprandially Sucralose Participants fasted before receiving treatment of 355 mL of water, 50 g of sucrose in 355 mL of water, 6 g of Splenda in 355 mL of water, or 50 g of sucrose and 6 g Splenda in 355 mL of water. Breakfast was given 1 h after treatment Sucralose, compared with water, had no significant effect on insulin, glucose, or glucagon levels Steinert et al (2011)55 Randomized, placebo-controlled, double-blinded, crossover trial Healthy individuals; n = 12; M and F; mean BMI 23 ± 0.5 kg/m2; mean age 23.3 ± 0.7 y Single dose on 6 occasions Sucralose, aspartame, acesulfame K Participants fasted before intragastric infusion of glucose (50 g in water), fructose (25 g in water), sucralose (62 mg in water), aspartame (169 mg in water), acesulfame K (220 mg in water), or control (250 mL of water) Sucralose, compared with water, had no significant effect on glucose, insulin, GLP-1, or appetite hormone response Ford et al (2011)56 Randomized, placebo-controlled, single-blinded, crossover trial Healthy individuals; M and F; n = 8; BMI 18.8–23.9 kg/m2; age 22–27 y Single dose on 3 occasions Sucralose Participants fasted before receiving treatment with 50 mL of water, 50 mL of sucralose (0.083% wt/vol), or 50 mL of sucralose (0.083% wt/vol) and maltodextrin (50% wt/vol), followed by modified sham-feeding protocol of same solution that was consumed to stimulate oral sweet receptors Consumption of sucralose or water, followed by modified sham feeding combined with sucralose, had no effect on plasma glucose, insulin, or GLP-1 concentrations. Consumption of sucralose with maltodextrin caused an increase in plasma glucose and insulin AUC without affecting GLP-1 Wu et al (2012)57 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 10; mean BMI 25.5 ± 1.5 kg/m2; mean age 28.8 ± 4.0 y Single dose on 4 occasions Sucralose Participants fasted before drinking preload drinks containing 40 g of glucose, 60 mg of sucralose, 40 g of 3-O-methylglucose, or 40 g of tagatose/isomalt mixture 15 min before consuming a labeled mashed potato meal containing 13C octanoic acid Sucralose had no effect on plasma blood glucose, GLP-1, GIP, or insulin Brown et al (2012)41 Randomized crossover trial 3 groups; M; age 13–24 y: Healthy participants: n = 25 Patients with T1DM: n = 9; mean BMI 21.7 ± 2.4 kg/m2 Obese patients with T2DM: n = 10; mean BMI 35.0 ± 6.8 kg/m2 Single dose on 2 occasions, administered postprandially (OGTT) Sucralose Participants fasted before consuming diet soda or carbonated water, Afterward, they consumed 240 mL of diet soda containing sucralose (190 ± 38 mg/mL) and acesulfame K (108 ± 0.6 mg/mL) or 240 mL of carbonated water as placeboOGTT with a 75-g glucose load was performed h after test drink was consumed T1DM individuals: GLP-1 AUC was 43% higher after diet soda consumption (P = 0.02)Healthy individuals: GLP-1 AUC was 34% higher after diet soda consumption (P = 0.029)All individuals: diet soda had no effect on glucose, C-peptides, or GIP Pepino et al (2013)44 Randomized crossover trial Morbidly obese individuals; M and F; n = 17; mean age 35.1 ± 1.0 y; mean BMI 41.0 ± 1.5 kg/m2; low consumption of NNSs (< 1 can of diet soda or < 1 spoonful of NNS per week) Single dose on 2 occasions, administered postprandially (OGTT) Sucralose After fasting, participants consumed either 60 mL of distilled water (control condition) or 60 mL of sucralose solution (2 mmol/L; 48 mg sucralose). OGTT with a 75-g glucose load was performed after treatment Glucose, insulin, and C-peptides were higher in sucralose group than in water group (P<0.004). Insulin sensitivity and insulin clearance both decreased: 23 ± 20% (P = 0.01) and 7 ± 4% (P = 0.04), respectively. No differences in GLP-1, GIP, or glucagon concentrations Wu et al (2013)58 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; M; mean BMI 25.5 ± 1.0 kg/m2; 33.6 ± 5.9 y Single dose on 4 occasions, administered in fasting state and postprandially (OGTT) Sucralose, acesulfame K Participants consumed either 240 mL of water alone or a similar amount of water sweetened with 52 mg of sucralose, 200 mg of acesulfame K, or 46 mg of sucralose and 26 mg of acesulfame K after an overnight fast. OGTT with 75 g of glucose and 150 mg of 13C-acetate was administered 10 min after each treatment Prior to glucose ingestion, blood glucose, plasma insulin, and GLP-1 levels remained unchanged after consumption of any of the sweetened drinks or water. Blood glucose, plasma insulin, and GLP-1 all increased after OGTT (P<0.001 for each) and were similar in all treatment groups Stellingwerff et al (2013)59 Randomized, double-blinded, crossover trial Healthy individuals; M; n = 23; mean BMI 23.1 ± 1.9 kg/m2; mean age 29 ± 7 y Single dose, given before, during, and after 2 h of exercise (cycling) Sucralose Eight 50-mL doses of either 1mM (20 mg) sucralose solution or placebo (sucralose mouthwash followed by drinking 50 mL of water) every 15 min for 2 h, starting 120 min prior to beginning of exercise Sucralose had no effect on blood glucose or insulin levels Temizkan et al (2015)60 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 8; mean age 45.0 ± 4.1 y; mean BMI 30.3 ± 4.5 kg/m2 Patients with newly diagnosed T2DM; M and F; n = 8; mean age 51.5 ± 9.2 y; mean BMI 33.7 ± 5.4 kg/m2 Single dose on 3 occasions, administered postprandially (OGTT) Sucralose, aspartame Participants consumed 24 mg of sucralose (tabletop formulation) in 200 mL of water or 72 mg of aspartame (tabletop formulation) in 200 mL of water or or 200 mL of water alone. OGTT (75 g of glucose) was performed 15 min after treatment Sucralose, compared with water, was associated with lower blood glucose AUC (P = 0.002) and increased GLP-1 AUC (P = 0.04) in healthy individuals No effect of sucralose on insulin or C-peptides levels No effect of sucralose on glucose, insulin, C-peptides, or GLP-1 in T2DM individuals Sylvetsky et al (2016)61 Randomized crossover trial Study arm 1: healthy individuals; n = 30; M and F; mean BMI 25.8 ± 4.2 kg/m2; mean age 29.7 ± 7.6 y Study arm 2: healthy individuals; n = 31; M and F; mean BMI 26.3 ± 7.5 kg/m2; mean age 27.4 ± 6.7 y Single dose, administered postprandially (OGTT) Sucralose, aspartame, acesulfame K Participants fasted before consuming beverages: Study arm 1: 355 mL of water alone; 355 mL of water plus sucralose (68 mg); 355 mL of water plus sucralose (170 mg); or 355 mL water plus sucralose (250 mg) Study arm 2: 355 mL of carbonated water alone; 355 mL of diet soda (18 mg sucralose + 18 mg acesulfame K + 57 mg aspartame + other ingredients); 355 mL of diet soda (68 mg sucralose + 41 mg acesulfame K + other ingredients); or 355 mL of carbonated water plus sucralose (68 mg) and acesulfame K (41 mg) Study arm 1: Sucralose preload of different doses had no effect on glucose, insulin, C-peptide, glucose absorption, or gut hormones GLP-1 and GIP. Carbonated water with NNSs, compared with carbonated water alone, also had no effect on the parameters measured Study arm 2: Sucralose preload with acesulfame K had no effect on metabolic outcomes. GLP-1 was increased after diet soda intake Grotz et al (2017)62 Randomized, double-blinded, parallel trial Healthy adults; n = 47; M; age 18–45 y; BMI 19.4–27.0 kg/m2 Repeated daily dose for 12 wk Sucralose Participants consumed capsules containing ≈ 333.3 mg of sucralose or placebo (cellulose), 3 times daily at mealtimes No differences between groups in change from baseline for fasting glucose, insulin, or HbA1c Romo-Romo et al (2018)63 Randomized, open-label, parallel-arm trial Healthy adults; n = 66; F; age 18–55 y; BMI 18.5–24.9 kg/m2; low consumers of NNSs (< 5 portions per week, regardless of product type) Repeated daily dose for 14 d Sucralose Participants consumed 1 commercial packet 3 times daily (12 mg sucralose, 958 mg dextrose, and 30 mg maltodextrin) added to beverage or meals. Control group consumed similar treatment, without sucralose Sucralose group showed significant decrease in insulin sensitivity compared with control group (P = 0.04). Acute insulin response increased in sucralose group (P = 0.04) Lertrit et al (2018)42 Randomized, double-blinded, crossover trial Healthy adults; n = 15; M and F; age 18–59 y; BMI 18.5–27 kg/m2 Repeated daily dose for 4 wk, admininstered postprandially (OGTT) Sucralose Participants consumed capsules containing 200 mg of sucralose or placebo Acute insulin response and sensitivity decreased in sucralose group (P<0.005). AUC of active GLP-1 increased in sucralose group (P<0.001) Nehrling et al (1985)64 Randomized, double-blinded, placebo-controlled trial Patients with IDDM or NIDD; n = 62; age 18–65 y Repeated daily dose for 18 wk Aspartame Participants consumed aspartame capsules (2.7 g) or placebo capsules (20 mg corn starch), daily with meals After treatment, blood glucose and HbA1c levels were similar in both groups Horwitz et al (1988)65 Randomized crossover trial Healthy individuals; F; n = 12; mean. age 28 ± 8 y; mean BMI 22.5 kg/m2 Patients with NIDDM on oral hypglycemic agents; F; n = 10; mean age 57 ± 8 y; mean BMI 33.7 kg/m2 Single dose on 3 occasions Aspartame, saccharin After an overnight fast, participants consumed 400 mg of aspartame and 300 mL of cherry-flavored Kool-Aid or 135 mg of saccharin and 300 mL of cherry-flavored Kool-Aid No significant changes in plasma glucose, insulin, or glucagon levels in any treatment group. In healthy participants, mean AUC insulin concentration was higher after aspartame consumption than after saccharin or control beverage consumption (P<0.05) Colagiuri et al (1989)66 Controlled, double-blinded, crossover trial NIDDM; M and F; n = 9; mean age 66 ± 5 y; mean BMI 26.4 ± 2.1 kg/m2 Repeated daily dose for 6 wk Aspartame, sucrose Participants consumed 45 g of sucrose and 162 mg of aspartame, added to meals and beverages daily Aspartame consumption did not cause changes in glucose and HbA1c levels Rodin (1990)67 Randomized crossover trial Overweight and normal-weight healthy individuals; n = 24; age 22–50 y Single dose Aspartame Participants consumed aspartame (250 mg) or fructose (50 g) or glucose (50 g) in 500 mL of water, or water alone as control No significant effects of aspartame on glucose, insulin, or glucagon levels Moller (1991)45 Randomized trial Healthy individuals; n = 6; M; age 22–37 y; weight 63–83 kg Single dose Aspartame Participants consumed aspartame (1 g) or bovine albumin (12.2 g) in 200 mL of water, or water alone as a control Aspartame, compared with control, resulted in decreased glucose concentrations (P<0.05). Insulin levels were not affected in any of the 3 groups Härtel et al (1993)68 Randomized clinical trial Healthy individuals; M and F; n = 14; age 19–52 y Single dose Aspartame, acesulfame K, saccharin Participants consumed 330 mL of water containing aspartame (165 mg), sucrose (33 g), acesulfame K (165 mg), cyclamate (800 mg), or saccharin (75 mg) NNS consumption, compared with sucrose consumption, had no effect on insulin or glucose concentrations Melanson et al (1999)46 Randomized, crossover trial Healthy individuals; n = 10; age 19–31 y; mean BMI 23.4 ± 1.9 kg/m2 Single dose Aspartame Participants consumed drinks containing aspartame, high fat, or carbohydrate, followed by ad libitum meals Blood glucose concentration decreased (P = 0.014) in 40% of participants after aspartame consumption Hall et al (2003)43 Crossover trial Healthy individuals; n = 6; age 24–31 y; BMI < 25 kg/m2 Single dose on 3 occasions Aspartame Participants consumed capsules containg aspartame (400 mg) or aspartic acid (176 mg) plus phenylalanine (224 mg) or control (400 mg of corn flour) Consumption of aspartame and amino acids resulted in decreased plasma GLP-1 (P<0.05). Aspartame did not affect glucose, insulin, or GIP concentrations Anton et al (2013)69 Crossover trial Healthy lean individuals; M and F; n = 19; age 18–50 y; BMI 20.0–24.9 kg/m2 Obese individuals; M and F; n = 12; age 18–50 y; BMI 30.0–39.9 kg/m2 Single dose on 3 occasions Aspartame, stevia, sucrose Participants consumed tea sweetened with aspartame or stevia or sucrose before they consumed a buffet-type meal ad libitum. Quantities were specified in kilocalories only, not milligrams Stevia, compared with sucrose, lowered plasma glucose and insulin levels (P<0.01 and P<0.05, respectively) Maersk et al (2012)70 Open crossover trial Healthy obese individuals; n = 24; mean age 33.5 ± 9.2 y; mean BMI 31.4 ± 3.11 kg/m2 Single dose on 4 occasions Aspartame Participants consumed 500 mL of a regular cola drink (sweetened with sucrose) or 500 mL of skimmed milk or 500 mL of a diet cola drink (sweetened with aspartame) or 500 mL of water Diet cola drink (sweetened with aspartame) had no effect on glucose, insulin, GLP-1, GIP, or ghrelin levels Olalde-Mendoza & Moreno-González (2013)71 Randomized trial Patients with T2DM on medication; n = 80; mean age 49.3 ± 9.0 y; mean BMI 30.5 ± 4.3 kg/m2 Single dose Aspartame, acesulfame K, regular (sugared) soda Participants consumed test beverage after an overnight fast: Group 1: 200 mL of of diet soda (containing 40 mg aspartame + 100 g acesulfame K) Group 2: 200 mL of regular soda (sweetened with sucrose) No effect of diet soda on capillary blood glucose levels Bryant et al (2014)72 Randomized crossover trial Healthy individuals; M and F; n = 10; age 18–24 y; mean BMI 21.8 ± 1.8 kg/m2 Single dose on 4 occasions Aspartame, saccharin, acesulfame K After an overnight fast, participants consumed a beverage containing the following in 250 mL of water: 45 g of glucose; 45 g of glucose and 150 mg of aspartame; 45 g of glucose and 85 mg of acesulfame K; or 45 g of glucose and 20 mg of saccharin NNS consumption had no effect on glucose concentrations Tey et al (2017)73 Randomized, double-blinded, crossover trial Healthy individuals; n = 30; M; age 21–50 y; BMI 18.5–25.0 kg/m2 Single dose on 1 occasions Aspartame, monk fruit extract, stevia, sucrose Participants consumed beverages given as preload containing the following: 0.44 g of aspartame and 500 mL of water; 0.63 g of monk fruit extract (50% mogroside) and 500 mL of water; 0.33 g of stevia (containing rebaudioside A, a steviol glycoside) and 500 mL of water; or 65 g of sucrose and 500 mL of water. Beverages were consumed 1 h before ad libitum lunch No effect of any treatment on glucose AUC or insulin AUC Higgins et al (2018)74 Randomized parallel-arm trial Healthy individuals; n = 93; M and F; age 18–60 y; BMI 18–25 kg/m2; not consumers of NNSs Repeated daily dose for 12 wk Aspartame Three groups of participants: Group that received no aspartame: took 2 capsules containing a total of 680 mg of dextrose and 80 mg of PABA plus 2 empty capsules Group that received 350 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 2 capsules containing a total of 680 mg of dextrose plus 2 empty capsules Group that received 1050 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 4 capsules containing a total of 700 mg of aspartame and 680 mg of dextrose No significant difference between groups in glucose, insulin, GLP-1, or GIP at baseline or week 12 Bonnet et al (2018)75 Randomized, double-blinded, crossover trial Healthy individuals; n = 50; M; mean age 31.1 ± 10.3 y; BMI 19–29 kg/m2; not regular consumers of NNSs (<1 can of beverage with high-intensity sweeteners per week) Repeated daily dose for 12 wk Aspartame, acesulfame K Participants consumed 330 mL of beverage containing 129 mg of aspartame and 13 mg of acesulfame K in carbonated water twice daily. Control group received 330 mL of carbonated water twice daily No significant difference between groups in insulin sensitivity or secretion Reference . Study design . Population characteristics . Duration of intervention . Type of NNS used . Dose of NNS used and method of administration . Main outcomes . Mezitis et al (1996)47 Randomized crossover trial Patients with T1DM or T2DM; M and F; n = 26; age < 65 y Single dose Sucralose Participants received sucralose (1000-mg capsule) or placebo (cellulose capsule), followed by a meal Sucralose consumption, compared with placebo, had no effect on glucose or C-peptide levels Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F Study 1: n = 8; mean age 32 y; mean weight 70 kg Repeated daily dose for 17 d Sucralose Participants fasted before the intervention. Sucralose supplied in aqueous solution (5 mg/mL) Phase 1: day 1: 0 mg/kg/d; day 3: 1.0 mg/kg/d; day 5: 2.5 mg/kg/d; day 7: 5 mg/kg/d; day 9: 10.0 mg/kg/d. Phase 2: day 11–13: 2.0 mg/kg/d; day 14–17: 5.0 mg/kg/d; day 18–25: 0 mg/kg/d No effect on fasting glucose or insulin Baird et al (2000)48 Randomized single-blinded trial Healthy adults; M and F, mean weight 71.5 kg Study 2, sucralose group: n = 77; mean age 34.6 y Study 2, control group: n = 31; mean age 33.9 y Repeated daily dose for 13 wk Sucralose Sucralose supplied in aqueous solution (5 mg/mL) and consumed twice daily for a total daily dose: Sucralose group: weeks 1–3: 125 mg/d; weeks 4–7: 250 mg/d, weeks 5–12: 500 mg/d Control group (fructose): weeks 1–13: 50 g/d No effect on fasting glucose or insulin Grotz et al (2003)49 Randomized, double-blinded, placebo-controlled trial Obese adults with T2DM; M and F; N = 136; age 31–70 y; mean BMI 31.6 kg/m2 Sucralose group: n = 67 Placebo group: n = 69 Repeated daily dose for 13 wk Follow-up: 4 wk Sucralose Sucralose group: 1 capsule containing sucralose (333.5 mg) supplied twice daily. Total daily intake was 667 mg Placebo group: 1 capsule containing cellulose, supplied twice daily Follow-up phase: 1 cellulose capsules, supplied daily No significant differences in plasma glucose, insulin, serum C-peptides, or HbA1c levels between sucralose and placebo groups over the entire study period Reyna et al (2003)50 Randomized, controlled clinical trial Adults with T2DM; M; mean age 45 ± 55 y Control group (ADA diet): n = 8; mean BMI 28.9 ± 2.0 kg/m2 Expermintal group (modified ADA diet): n = 8; mean BMI 28.5 ± 1.7 kg/m2 Repeated daily dose for 4 wk Sucralose ADA diet: components of diet not mentioned Modified diet: fructose and sucralose were used as sweeteners in a ratio of 30 to 70 Low-calorie diet: included fat-free bread with 8% fat replacer with β-glucans and oats, and cookies prepared with 50% fat replacer with β-glucans. Bread was consumed twice daily (60 g) each bread and 3 cookies (20 g/cookie) Significant improvement in HbA1c, lipid profile, and BMI, but not in fasting blood glucose, in both groups. Sucralose-containing diet resulted in greater improvement than the ADA diet, with a greater decrease in HbA1c Ma et al (2009)51 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 7; mean BMI 21.6 ± 1.2 kg/m2; mean age 24 ± 2 y Single dose on 4 occasions Sucralose All participants received intragastric infusion labeled with 150 mg of 13C-acetate: 500 mL of saline, 50 g of sucrose (positive control), 80 mg of sucralose, or 800 mg of sucralose Sucralose, when consumed alone, had no effect on blood glucose, insulin, plasma GLP-1, or GIP levels Brown et al (2009)52 Randomized crossover trial Healthy individuals; M and F; n = 22; mean BMI 25.6 ± 4.6 kg/m2; age 12–25 y Single dose, administered postprandially (OGTT) Sucralose Participants fasted before treatment and then ingested either 240 mL of carbonated water or 240 mL of diet drink containing sucralose (unknown concentration) and acesulfame K. Ten minutes after treatment, OGTT with 75 g of glucose was performed No effect of sucralose on glucose, insulin, GLP-1, or C-peptides following OGTT. GLP-1 peak (P = 0.003) and AUC (P = 0.003) were significantly higher with diet soda than with carbonated water Ma et al (2010)53 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; mean BMI 23.4 ± 0.8 kg/m2; mean age 27 ± 2 y Single dose on 2 occasions Sucralose Participants received intraduodenal infusion of either sucralose (960 mg) in saline or saline only for 150 min Sucralose infusion did not affect glucose or GLP-1 Brown et al (2011)54 Randomized crossover trial Healthy individuals; n = 8; F; mean BMI 22.1 ± 1.7 kg/m2; mean age 21.8 ± 2.5 y Single dose on 4 occasions, administered in fasting state and postprandially Sucralose Participants fasted before receiving treatment of 355 mL of water, 50 g of sucrose in 355 mL of water, 6 g of Splenda in 355 mL of water, or 50 g of sucrose and 6 g Splenda in 355 mL of water. Breakfast was given 1 h after treatment Sucralose, compared with water, had no significant effect on insulin, glucose, or glucagon levels Steinert et al (2011)55 Randomized, placebo-controlled, double-blinded, crossover trial Healthy individuals; n = 12; M and F; mean BMI 23 ± 0.5 kg/m2; mean age 23.3 ± 0.7 y Single dose on 6 occasions Sucralose, aspartame, acesulfame K Participants fasted before intragastric infusion of glucose (50 g in water), fructose (25 g in water), sucralose (62 mg in water), aspartame (169 mg in water), acesulfame K (220 mg in water), or control (250 mL of water) Sucralose, compared with water, had no significant effect on glucose, insulin, GLP-1, or appetite hormone response Ford et al (2011)56 Randomized, placebo-controlled, single-blinded, crossover trial Healthy individuals; M and F; n = 8; BMI 18.8–23.9 kg/m2; age 22–27 y Single dose on 3 occasions Sucralose Participants fasted before receiving treatment with 50 mL of water, 50 mL of sucralose (0.083% wt/vol), or 50 mL of sucralose (0.083% wt/vol) and maltodextrin (50% wt/vol), followed by modified sham-feeding protocol of same solution that was consumed to stimulate oral sweet receptors Consumption of sucralose or water, followed by modified sham feeding combined with sucralose, had no effect on plasma glucose, insulin, or GLP-1 concentrations. Consumption of sucralose with maltodextrin caused an increase in plasma glucose and insulin AUC without affecting GLP-1 Wu et al (2012)57 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 10; mean BMI 25.5 ± 1.5 kg/m2; mean age 28.8 ± 4.0 y Single dose on 4 occasions Sucralose Participants fasted before drinking preload drinks containing 40 g of glucose, 60 mg of sucralose, 40 g of 3-O-methylglucose, or 40 g of tagatose/isomalt mixture 15 min before consuming a labeled mashed potato meal containing 13C octanoic acid Sucralose had no effect on plasma blood glucose, GLP-1, GIP, or insulin Brown et al (2012)41 Randomized crossover trial 3 groups; M; age 13–24 y: Healthy participants: n = 25 Patients with T1DM: n = 9; mean BMI 21.7 ± 2.4 kg/m2 Obese patients with T2DM: n = 10; mean BMI 35.0 ± 6.8 kg/m2 Single dose on 2 occasions, administered postprandially (OGTT) Sucralose Participants fasted before consuming diet soda or carbonated water, Afterward, they consumed 240 mL of diet soda containing sucralose (190 ± 38 mg/mL) and acesulfame K (108 ± 0.6 mg/mL) or 240 mL of carbonated water as placeboOGTT with a 75-g glucose load was performed h after test drink was consumed T1DM individuals: GLP-1 AUC was 43% higher after diet soda consumption (P = 0.02)Healthy individuals: GLP-1 AUC was 34% higher after diet soda consumption (P = 0.029)All individuals: diet soda had no effect on glucose, C-peptides, or GIP Pepino et al (2013)44 Randomized crossover trial Morbidly obese individuals; M and F; n = 17; mean age 35.1 ± 1.0 y; mean BMI 41.0 ± 1.5 kg/m2; low consumption of NNSs (< 1 can of diet soda or < 1 spoonful of NNS per week) Single dose on 2 occasions, administered postprandially (OGTT) Sucralose After fasting, participants consumed either 60 mL of distilled water (control condition) or 60 mL of sucralose solution (2 mmol/L; 48 mg sucralose). OGTT with a 75-g glucose load was performed after treatment Glucose, insulin, and C-peptides were higher in sucralose group than in water group (P<0.004). Insulin sensitivity and insulin clearance both decreased: 23 ± 20% (P = 0.01) and 7 ± 4% (P = 0.04), respectively. No differences in GLP-1, GIP, or glucagon concentrations Wu et al (2013)58 Randomized, single-blinded, crossover trial Healthy individuals; n = 10; M; mean BMI 25.5 ± 1.0 kg/m2; 33.6 ± 5.9 y Single dose on 4 occasions, administered in fasting state and postprandially (OGTT) Sucralose, acesulfame K Participants consumed either 240 mL of water alone or a similar amount of water sweetened with 52 mg of sucralose, 200 mg of acesulfame K, or 46 mg of sucralose and 26 mg of acesulfame K after an overnight fast. OGTT with 75 g of glucose and 150 mg of 13C-acetate was administered 10 min after each treatment Prior to glucose ingestion, blood glucose, plasma insulin, and GLP-1 levels remained unchanged after consumption of any of the sweetened drinks or water. Blood glucose, plasma insulin, and GLP-1 all increased after OGTT (P<0.001 for each) and were similar in all treatment groups Stellingwerff et al (2013)59 Randomized, double-blinded, crossover trial Healthy individuals; M; n = 23; mean BMI 23.1 ± 1.9 kg/m2; mean age 29 ± 7 y Single dose, given before, during, and after 2 h of exercise (cycling) Sucralose Eight 50-mL doses of either 1mM (20 mg) sucralose solution or placebo (sucralose mouthwash followed by drinking 50 mL of water) every 15 min for 2 h, starting 120 min prior to beginning of exercise Sucralose had no effect on blood glucose or insulin levels Temizkan et al (2015)60 Randomized, single-blinded, crossover trial Healthy individuals; M and F; n = 8; mean age 45.0 ± 4.1 y; mean BMI 30.3 ± 4.5 kg/m2 Patients with newly diagnosed T2DM; M and F; n = 8; mean age 51.5 ± 9.2 y; mean BMI 33.7 ± 5.4 kg/m2 Single dose on 3 occasions, administered postprandially (OGTT) Sucralose, aspartame Participants consumed 24 mg of sucralose (tabletop formulation) in 200 mL of water or 72 mg of aspartame (tabletop formulation) in 200 mL of water or or 200 mL of water alone. OGTT (75 g of glucose) was performed 15 min after treatment Sucralose, compared with water, was associated with lower blood glucose AUC (P = 0.002) and increased GLP-1 AUC (P = 0.04) in healthy individuals No effect of sucralose on insulin or C-peptides levels No effect of sucralose on glucose, insulin, C-peptides, or GLP-1 in T2DM individuals Sylvetsky et al (2016)61 Randomized crossover trial Study arm 1: healthy individuals; n = 30; M and F; mean BMI 25.8 ± 4.2 kg/m2; mean age 29.7 ± 7.6 y Study arm 2: healthy individuals; n = 31; M and F; mean BMI 26.3 ± 7.5 kg/m2; mean age 27.4 ± 6.7 y Single dose, administered postprandially (OGTT) Sucralose, aspartame, acesulfame K Participants fasted before consuming beverages: Study arm 1: 355 mL of water alone; 355 mL of water plus sucralose (68 mg); 355 mL of water plus sucralose (170 mg); or 355 mL water plus sucralose (250 mg) Study arm 2: 355 mL of carbonated water alone; 355 mL of diet soda (18 mg sucralose + 18 mg acesulfame K + 57 mg aspartame + other ingredients); 355 mL of diet soda (68 mg sucralose + 41 mg acesulfame K + other ingredients); or 355 mL of carbonated water plus sucralose (68 mg) and acesulfame K (41 mg) Study arm 1: Sucralose preload of different doses had no effect on glucose, insulin, C-peptide, glucose absorption, or gut hormones GLP-1 and GIP. Carbonated water with NNSs, compared with carbonated water alone, also had no effect on the parameters measured Study arm 2: Sucralose preload with acesulfame K had no effect on metabolic outcomes. GLP-1 was increased after diet soda intake Grotz et al (2017)62 Randomized, double-blinded, parallel trial Healthy adults; n = 47; M; age 18–45 y; BMI 19.4–27.0 kg/m2 Repeated daily dose for 12 wk Sucralose Participants consumed capsules containing ≈ 333.3 mg of sucralose or placebo (cellulose), 3 times daily at mealtimes No differences between groups in change from baseline for fasting glucose, insulin, or HbA1c Romo-Romo et al (2018)63 Randomized, open-label, parallel-arm trial Healthy adults; n = 66; F; age 18–55 y; BMI 18.5–24.9 kg/m2; low consumers of NNSs (< 5 portions per week, regardless of product type) Repeated daily dose for 14 d Sucralose Participants consumed 1 commercial packet 3 times daily (12 mg sucralose, 958 mg dextrose, and 30 mg maltodextrin) added to beverage or meals. Control group consumed similar treatment, without sucralose Sucralose group showed significant decrease in insulin sensitivity compared with control group (P = 0.04). Acute insulin response increased in sucralose group (P = 0.04) Lertrit et al (2018)42 Randomized, double-blinded, crossover trial Healthy adults; n = 15; M and F; age 18–59 y; BMI 18.5–27 kg/m2 Repeated daily dose for 4 wk, admininstered postprandially (OGTT) Sucralose Participants consumed capsules containing 200 mg of sucralose or placebo Acute insulin response and sensitivity decreased in sucralose group (P<0.005). AUC of active GLP-1 increased in sucralose group (P<0.001) Nehrling et al (1985)64 Randomized, double-blinded, placebo-controlled trial Patients with IDDM or NIDD; n = 62; age 18–65 y Repeated daily dose for 18 wk Aspartame Participants consumed aspartame capsules (2.7 g) or placebo capsules (20 mg corn starch), daily with meals After treatment, blood glucose and HbA1c levels were similar in both groups Horwitz et al (1988)65 Randomized crossover trial Healthy individuals; F; n = 12; mean. age 28 ± 8 y; mean BMI 22.5 kg/m2 Patients with NIDDM on oral hypglycemic agents; F; n = 10; mean age 57 ± 8 y; mean BMI 33.7 kg/m2 Single dose on 3 occasions Aspartame, saccharin After an overnight fast, participants consumed 400 mg of aspartame and 300 mL of cherry-flavored Kool-Aid or 135 mg of saccharin and 300 mL of cherry-flavored Kool-Aid No significant changes in plasma glucose, insulin, or glucagon levels in any treatment group. In healthy participants, mean AUC insulin concentration was higher after aspartame consumption than after saccharin or control beverage consumption (P<0.05) Colagiuri et al (1989)66 Controlled, double-blinded, crossover trial NIDDM; M and F; n = 9; mean age 66 ± 5 y; mean BMI 26.4 ± 2.1 kg/m2 Repeated daily dose for 6 wk Aspartame, sucrose Participants consumed 45 g of sucrose and 162 mg of aspartame, added to meals and beverages daily Aspartame consumption did not cause changes in glucose and HbA1c levels Rodin (1990)67 Randomized crossover trial Overweight and normal-weight healthy individuals; n = 24; age 22–50 y Single dose Aspartame Participants consumed aspartame (250 mg) or fructose (50 g) or glucose (50 g) in 500 mL of water, or water alone as control No significant effects of aspartame on glucose, insulin, or glucagon levels Moller (1991)45 Randomized trial Healthy individuals; n = 6; M; age 22–37 y; weight 63–83 kg Single dose Aspartame Participants consumed aspartame (1 g) or bovine albumin (12.2 g) in 200 mL of water, or water alone as a control Aspartame, compared with control, resulted in decreased glucose concentrations (P<0.05). Insulin levels were not affected in any of the 3 groups Härtel et al (1993)68 Randomized clinical trial Healthy individuals; M and F; n = 14; age 19–52 y Single dose Aspartame, acesulfame K, saccharin Participants consumed 330 mL of water containing aspartame (165 mg), sucrose (33 g), acesulfame K (165 mg), cyclamate (800 mg), or saccharin (75 mg) NNS consumption, compared with sucrose consumption, had no effect on insulin or glucose concentrations Melanson et al (1999)46 Randomized, crossover trial Healthy individuals; n = 10; age 19–31 y; mean BMI 23.4 ± 1.9 kg/m2 Single dose Aspartame Participants consumed drinks containing aspartame, high fat, or carbohydrate, followed by ad libitum meals Blood glucose concentration decreased (P = 0.014) in 40% of participants after aspartame consumption Hall et al (2003)43 Crossover trial Healthy individuals; n = 6; age 24–31 y; BMI < 25 kg/m2 Single dose on 3 occasions Aspartame Participants consumed capsules containg aspartame (400 mg) or aspartic acid (176 mg) plus phenylalanine (224 mg) or control (400 mg of corn flour) Consumption of aspartame and amino acids resulted in decreased plasma GLP-1 (P<0.05). Aspartame did not affect glucose, insulin, or GIP concentrations Anton et al (2013)69 Crossover trial Healthy lean individuals; M and F; n = 19; age 18–50 y; BMI 20.0–24.9 kg/m2 Obese individuals; M and F; n = 12; age 18–50 y; BMI 30.0–39.9 kg/m2 Single dose on 3 occasions Aspartame, stevia, sucrose Participants consumed tea sweetened with aspartame or stevia or sucrose before they consumed a buffet-type meal ad libitum. Quantities were specified in kilocalories only, not milligrams Stevia, compared with sucrose, lowered plasma glucose and insulin levels (P<0.01 and P<0.05, respectively) Maersk et al (2012)70 Open crossover trial Healthy obese individuals; n = 24; mean age 33.5 ± 9.2 y; mean BMI 31.4 ± 3.11 kg/m2 Single dose on 4 occasions Aspartame Participants consumed 500 mL of a regular cola drink (sweetened with sucrose) or 500 mL of skimmed milk or 500 mL of a diet cola drink (sweetened with aspartame) or 500 mL of water Diet cola drink (sweetened with aspartame) had no effect on glucose, insulin, GLP-1, GIP, or ghrelin levels Olalde-Mendoza & Moreno-González (2013)71 Randomized trial Patients with T2DM on medication; n = 80; mean age 49.3 ± 9.0 y; mean BMI 30.5 ± 4.3 kg/m2 Single dose Aspartame, acesulfame K, regular (sugared) soda Participants consumed test beverage after an overnight fast: Group 1: 200 mL of of diet soda (containing 40 mg aspartame + 100 g acesulfame K) Group 2: 200 mL of regular soda (sweetened with sucrose) No effect of diet soda on capillary blood glucose levels Bryant et al (2014)72 Randomized crossover trial Healthy individuals; M and F; n = 10; age 18–24 y; mean BMI 21.8 ± 1.8 kg/m2 Single dose on 4 occasions Aspartame, saccharin, acesulfame K After an overnight fast, participants consumed a beverage containing the following in 250 mL of water: 45 g of glucose; 45 g of glucose and 150 mg of aspartame; 45 g of glucose and 85 mg of acesulfame K; or 45 g of glucose and 20 mg of saccharin NNS consumption had no effect on glucose concentrations Tey et al (2017)73 Randomized, double-blinded, crossover trial Healthy individuals; n = 30; M; age 21–50 y; BMI 18.5–25.0 kg/m2 Single dose on 1 occasions Aspartame, monk fruit extract, stevia, sucrose Participants consumed beverages given as preload containing the following: 0.44 g of aspartame and 500 mL of water; 0.63 g of monk fruit extract (50% mogroside) and 500 mL of water; 0.33 g of stevia (containing rebaudioside A, a steviol glycoside) and 500 mL of water; or 65 g of sucrose and 500 mL of water. Beverages were consumed 1 h before ad libitum lunch No effect of any treatment on glucose AUC or insulin AUC Higgins et al (2018)74 Randomized parallel-arm trial Healthy individuals; n = 93; M and F; age 18–60 y; BMI 18–25 kg/m2; not consumers of NNSs Repeated daily dose for 12 wk Aspartame Three groups of participants: Group that received no aspartame: took 2 capsules containing a total of 680 mg of dextrose and 80 mg of PABA plus 2 empty capsules Group that received 350 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 2 capsules containing a total of 680 mg of dextrose plus 2 empty capsules Group that received 1050 mg of aspartame daily: drank beverage containing 350 mg of aspartame and 80 mg of PABA and took 4 capsules containing a total of 700 mg of aspartame and 680 mg of dextrose No significant difference between groups in glucose, insulin, GLP-1, or GIP at baseline or week 12 Bonnet et al (2018)75 Randomized, double-blinded, crossover trial Healthy individuals; n = 50; M; mean age 31.1 ± 10.3 y; BMI 19–29 kg/m2; not regular consumers of NNSs (<1 can of beverage with high-intensity sweeteners per week) Repeated daily dose for 12 wk Aspartame, acesulfame K Participants consumed 330 mL of beverage containing 129 mg of aspartame and 13 mg of acesulfame K in carbonated water twice daily. Control group received 330 mL of carbonated water twice daily No significant difference between groups in insulin sensitivity or secretion Abbreviations: acesulfame K; acesulfame potassium; ADA, American Diabetes Association; AUC, area under the curve; BMI, body mass index; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; HbA1c, hemoglobin A1c; IDDM, insulin-dependent diabetes mellitus; NIDD, non-insulin-dependent diabetes; NIDDM, non-insulin-dependent diabetes mellitus; OGTT, oral glucose tolerance test; PABA, para-amino benzoic acid; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. Open in new tab Cephalic phase insulin response When humans ingest a sweet meal, the activation of oral sweet receptors will send sensory information to the brain, which in turn will cause the release of insulin76 to prepare the body for energy metabolism.77,78 These physiological responses, which last for approximately 10 minutes, are known as the cephalic phase insulin response and have been demonstrated in human and animal studies.79–82 In their study in humans, Ahren and Holst83 showed the importance of the cephalic phase insulin response to meal ingestion for postmeal glucose tolerance. Moreover, blocking of the cephalic phase insulin response caused a prolonged increase in blood glucose concentrations. Some NNSs stimulate the cephalic phase insulin response, while others do not. For example, activation of oral taste receptors via mouthwash solutions sweetened with saccharin activates a cephalic phase insulin response and causes a significant increase in the plasma insulin concentration.84 In other studies, however, the presence of sucralose, aspartame, or saccharin did not activate the cephalic phase insulin responses56,68; however, further studies are needed to confirm these findings. In humans, it was reported that oral sensory stimulation with food significantly lowered the plasma glucose area under the curve (AUC) (P < 0.03) in healthy humans. This suggests that oral sensory stimulation is important for glucose metabolism and homeostasis.80 If NNSs stimulate oral sweet taste receptors and activate the cephalic phase insulin response when no sugar is present,84 this could lead to changes in glucose metabolism as well as depressed hormonal responses with regular use of NNSs. Non-nutritive sweeteners are usually consumed in foods or beverages, and thus consumption of NNS-containing foods or beverages could stimulate the cephalic phase insulin response. When conducting a clinical trial involving NNSs, it is important to consider the route of delivery. For example, administering an NNS in capsule form may not trigger the cephalic phase insulin response and thus may not mimic actual NNS consumption. Gut microbiota The human gut microbiota is a collection of microorganisms that live symbiotically with the digestive tract. It is estimated that the human gut microbiota could consist of as many as 100 trillion bacteria (1014) in the large intestine.85 Colonization of the microbiota begins in the proximal gastrointestinal tract, starting in the stomach and ending with an enormous number of diverse microorganisms in the distal gastrointestinal tract, or the colon. Every host has a specific microbial community that evolves rapidly throughout its life and can be affected by external and internal modifications,86 mainly exposure to host diet and xenobiotics. The evolution of the gut microbiota in humans might involve changes on different scales, such as alterations within the microbial community, the evolution of microbial genomes within an individual, and exchanges between the microbiota and the physical environment outside the host.87 Up to 90% of the adult human gut microbiota is dominated by 2 bacterial phyla: the Bacteroidetes and the Firmicutes, whereas Actinobacteria, Proteobacteria, Verrucomicrobia, Fusobacteria and Cyanobacteria represent the bacterial minority.88 Gut microbiota have many different physiological roles, including maintenance of the immune system, regulation of gastrointestinal tract motility, metabolization of drugs, defense against pathogens, production of vitamins, metabolization of carbohydrates, and metabolization of indigestible polysaccharides into short-chain fatty acids, such as propionate, acetate, and butyrate.89,90 A shift in the quality, quantity, or composition of the gut microbiome (referred to as gut microbiota dysbiosis) can interfere with these roles.91 Westernized diets, which are rich in fat and sugar, along with a sedentary lifestyle have been linked to intestinal dysbiosis, which can lead to impaired glycemic control.92 Exposure to NNSs has also been shown to cause dysbiosis. For example, repeated exposure to the NNS saccharin in mouse models induces glucose intolerance by altering the microbial composition of the gut.93 The gut microbiota has the ability to metabolize NNS saccharin into short-chain fatty acids, which may have a wide range of consequences, including the potential to shift the normal bacterial balance and to produce absorbable by-products of short-chain fatty acids that may provide calories.94 Some NNSs have been shown to exert a bacteriostatic effect on the gut microbiota, leading to dysbiosis, at least in rodent models.21,27 For example, Abou-Donia et al27 reported that administration of Splenda (which contains sucralose) by oral gavage at different concentrations of up to 1000 mg/kg for 12 weeks in rats resulted in a significant decrease in beneficial gut bacteria. Moreover, this decrease was sustained during the 12-week recovery period.27 Furthermore, Palmnas et al21 examined the effect of low-dose aspartame consumption on the gut microbiota of rats. Fecal analysis showed that daily consumption of aspartame (5–7 mg/kg/d) for 8 weeks resulted in an increase in the total bacterial content, especially counts of Enterobacteriaceae and Clostridium leptum.21 Consumption of NNSs has also been linked to an increased risk of weight gain, obesity, T2DM, metabolic syndrome, and cardiovascular events in humans.95 These negative health effects may be partially related to alterations in glucose metabolism. Suez et al93 demonstrated that glycemic responses in 4 of 7 healthy individuals who consumed the FDA’s maximal ADI of the NNS saccharin during a 5-day period were significantly worse after the intervention. Furthermore, microbiome analysis of all 7 participants showed that so-called NNS responders (those who developed poor glycemic responses) had pronounced changes in the composition of their microbiota, whereas NNS nonresponders showed little change.93 In the same study, the authors also showed how NNS consumption is associated with changes in glucose metabolism that are mediated by gut microbiota dysbiosis by transplanting fecal microbiota from saccharin-consuming mice into germ-free mice. When compared with controls, mice that received a microbiota transplant from saccharin-treated mice developed glucose intolerance.93 Few clinical trials have investigated the effect of NNSs on the human gut microbiota. More studies on this topic are needed, particularly since the association between dietary habits, gut microbiota, and human health has been established.96 Advancements in molecular and microbial DNA sequencing techniques have enabled better research of microbial communities.97 RANDOMIZED CLINICAL TRIALS MEASURING THE EFFECTS OF ASPARTAME AND SUCRALOSE ON GLUCOSE METABOLISM AND GUT HORMONES Interest in the impact of NNS consumption on glucose metabolism has increased, as evidenced by in vitro and in vivo animals studies investigating the effects of NNSs on the incretin hormones GLP-1 and GIP (both of which influence glucose absorption and metabolism).36,37 The number of human studies evaluating the effects of repeated daily exposure to sucralose or aspartame on glucose metabolism is far fewer than the number of studies evaluating the effects of an acute single dose of NNS. Human trials are summarized in Table 2. Studies evaluating the effect of repeated doses of sucralose on glucose metabolism The effect of repeated doses of sucralose has been assessed in healthy, obese, and diabetic participants. Baird et al48 evaluated the effect of different doses of sucralose in 2 single-blinded, randomized trials in healthy human participants. In the first study, increasing doses of sucralose (1.0, 2.5, 5.0, and 10.0 mg/kg) were given to healthy volunteers (n = 8) every other day for 10 days, followed by a daily dose at 2 mg/kg for 3 days and 5 mg/kg for 4 days (total duration, 17 days). In the second study, participants consumed up to 500 mg of sucralose per day (n = 77) or 50 g of fructose per day (n = 31), twice daily for 13 weeks. The results demonstrated that sucralose had no effect on fasting insulin or blood glucose levels over the course of both studies.48 Even though the dose of sucralose used in the second study was high compared with the ADI, there was no effect on glucose or insulin after prolonged exposure. Participants were not screened for past NNS use. Consistent with Baird et al,48 Grotz et al49 found no effect of sucralose on glucose metabolism. Obese participants with T2DM (n = 136) were randomly assigned to receive either encapsulated sucralose (333.5 mg) twice daily for 13 weeks or placebo (cellulose capsules for the same period). All participants received placebo capsules during the last 4 weeks of the 6-week screening period, which took place prior to the 13-week test period, and during the entire 4-week follow-up period. There were no significant differences in fasting plasma glucose, hemoglobin A1c (HbA1c), or C-peptides from baseline or throughout the experiment between the sucralose and placebo groups.49 The sucralose dose used in this study was 3 times the estimated maximum intake (2.4 mg/kg/d), yet there was no effect of repeated daily consumption of sucralose. Participants were not screened for past NNS use. Reyna et al50 conducted a study in male patients with well-controlled T2DM (n = 16) to compare metabolic and anthropometric changes induced by a diet based on the American Diabetes Association’s nutritional recommendations vs a modified, low-calorie diet containing a fat replacement, sucralose, and fructose. Both groups received the experimental diet for 4 weeks and performed daily aerobic exercise (60 minutes of walking). After 4 weeks, both groups showed significant improvement in HbA1c, body weight, body mass index, and lipid profile, but not in fasting blood glucose; however, greater improvement was observed in the group who received the low-calorie diet containing sucralose.50 The amount of sucralose used in this trial, however, was not reported. It also cannot be confirmed whether the improvements observed in group that received the sucralose-containing diet were related to the sucralose, because the composition of the 2 diets was different. Grotz et al62 examined the effect of repeated doses of sucralose on glucose and insulin HbA1c levels in healthy male volunteers (n = 47) in a randomized, double-blinded, placebo-controlled study. Participants consumed encapsulated sucralose (333.3 mg) or placebo 3 times daily at mealtimes for 12 weeks. No differences in fasting glucose, insulin, or HbA1c concentrations were observed between the sucralose and placebo groups.62 However, NNSs given in capsule form bypass the activation of oral sweet taste receptors, which might have affected the outcomes. The sucralose concentration used in this trial exceeded the ADI for sucralose. The effect of repeated doses of sucralose has been assessed in healthy and diabetic participants (Table 2). Romo-Romo et al63 conducted a randomized, open-label, parallel-arm study to measure the effects of sucralose ingestion on blood glucose, plasma insulin, and insulin sensitivity. Healthy female participants (n = 66) received a commercial sucralose packet (958 mg of dextrose, 30 mg of maltodextrin, and 12 mg of sucralose) 3 times daily for 14 days. Insulin sensitivity was lower in the sucralose group than in the control group (P = 0.04). Moreover, the acute insulin response was greater in the sucralose group (P = 0.04) than in the control group.63 However, the amount and contents of the packets given to the control group were not mentioned; therefore, these results should be interpreted with caution. Lertrit et al42 conducted a study to measure the effects of repeated consumption of sucralose on glycemic response, insulin secretion and sensitivity, and GLP-1 secretion in a randomized, crossover, double-blinded trial of 15 healthy participants who received sucralose capsules (200 mg) or empty placebo capsules for 4 weeks. They reported that AUCs for GLP-1 were higher in the sucralose group than in the control group (P < 0.001) and that the acute insulin response and insulin sensitivity were lower in the sucralose group than in the control group (P < 0.005) after an oral glucose tolerance test with 75 g of glucose was performed the next morning.42 The delivery of the NNS in capsule form, however, bypasses the oral sweet taste receptors, and this may have played a role in the outcomes measured. In summary, the majority of the clinical trials that examined repeated daily consumption of sucralose by healthy and diabetic patients showed no significant effects on blood glucose, insulin, or C-peptides.48–50 Nevertheless, these studies had several limitations: (1) participants were not screened for past NNS use; (2) sucralose was given in capsule form; and (3) in 1 trial, neither the amount of NNS used nor information about the presence of other ingredients was provided. Studies evaluating the effect of a single dose of sucralose on glucose metabolism The effects of a single dose of sucralose on blood glucose, insulin, and gut hormones in healthy and diabetic patients have been evaluated in many studies. In a randomized crossover trial, Mezitis et al47 found that sucralose ingestion, compared with placebo, has no effect on glucose or C-peptide concentrations. Participants with type 1 diabetes mellitus (T1DM) (n = 13) or T2DM (n = 13) were recruited to receive a single dose of sucralose (1000-mg capsule) or placebo (cellulose capsules) followed by a meal. The results showed that sucralose consumption had no effect on glucose or C-peptide levels compared with placebo.47 However, in this study, sucralose was administered in capsule form. Ma et al51 conducted a randomized, single-blinded, crossover study to measure the effect of sucralose on blood glucose levels, release of the incretin hormones GLP-1 and GIP, and insulin release in healthy male and female participants (n = 7). All participants were fasted and received an intragastric infusion of saline (500 mL), sucrose (50 g), or sucralose (80 mg or 800 mg), all of which were labeled with 150 mg of 13C-acetate. The results showed that the sucralose and saline solutions had no effect on blood glucose, insulin, GLP-1, or GIP levels.51 The bypassing of oral activation of sweet taste receptors, however, might have affected the results. Brown et al52 conducted a randomized crossover trial in healthy male and female participants (n = 22) to determine the effects of a single doses of sucralose on glucose metabolism. The fasted volunteers received either 240 mL of diet soda containing sucralose of an unknown concentration with acesulfame K or 240 mL of carbonated water. An oral glucose tolerance test with 75 g of glucose was performed 10 minutes after participants consumed the drinks. No effect of sucralose or acesulfame K consumption on glucose, insulin, GLP-1, or C-peptides was observed. However, after the oral glucose load, the GLP-1 peak (P = 0.003) and the AUC (P = 0.003) were significantly higher with diet soda than with carbonated water.52,54 The other ingredients in diet soda (including color, caramel, natural flavors, citric acid, potassium benzoate, phosphoric acid, potassium citrate, and gum acacia) might have interfered with the effects observed and should be controlled for in studies looking to replicate this effect. Additionally, the sucralose concentration was not reported in this trial, and participants were not screened for past NNS use. Ma et al53 conducted a randomized, single-blinded, crossover study to measure the acute effects of sucralose on glucose absorption in healthy male and female participants (n = 10). Each participant was infused intraduodenally with either sucralose (960 mg) or control (0.9% saline) at 4 mL/min for 150 minutes. The results showed no significant difference in blood glucose or GLP-1 levels between the NNS and saline infusions.53 However, sucralose delivered intraduodenally bypasses the activation of oral sweet receptors, which does not replicate the normal route of consumption of sucralose. In addition, Brown et al54 conducted a randomized crossover trial in healthy women (n = 8) to determine the acute effect of sucralose on blood glucose, insulin, and glucagon in fasting and postprandial states. Participants consumed sucrose and/or sucralose dissolved in water in a factorial design consisting of water only (355 mL), sucrose (50 g) in 355 mL of water, Splenda (6 g) in 355 mL of water, or sucrose (50 g) and Splenda (6 g) in 355 mL of water. The results showed no significant effect of sucralose on insulin, glucose, or glucagon compared with water alone.54 In this study, however, past NNS use was not measured. Steinert et al55 conducted a double-blinded, placebo-controlled, crossover study in healthy male and female participants (n = 12) to measure the acute effect of NNSs on blood glucose, insulin, GLP-1, and appetite hormones. After an overnight fast, each participant received one of the following treatments dissolved in 250 mL of water by intragastric infusion: glucose (50 g in water), fructose (25 g in water), sucralose (62 mg in water), aspartame (169 mg in water), or acesulfame K (220 mg in water), with water alone used as control. No glucose, insulin, GLP-1, or appetite hormone response was observed when NNSs were administered.55 Again, however, there was no screening for past NNS use in this study. Ford et al56 conducted a randomized, single-blinded, placebo-controlled crossover trial in healthy male and female participants (n = 8) to investigate the acute effect of oral sucralose consumption on plasma glucose, insulin, and GLP-1. After an overnight fast, participants received 50 mL of water, 50 mL of sucralose (0.083% wt/vol), or 50 mL of sucralose (0.083% wt/vol) plus maltodextrin (50% wt/vol), followed by a modified sham feeding of the same solution that was consumed to stimulate oral sweet receptors. Consumption of sucralose or water followed by the modified sham feeding had no effect on plasma levels of glucose, insulin, or GLP-1. However, consumption of sucralose plus maltodextrin caused an increase in plasma glucose and insulin AUCs without affecting the GLP-1 hormone.56 Past use of NNSs may have affected the results of this study, but no screening was conducted. Wu et al57 assessed the acute effects of different types of sweet preload drinks (drinks containing small loads of macronutrients given at fixed intervals before a meal) on blood glucose, insulin, and incretin hormone secretion in a randomized, single-blinded trial. After fasting, healthy male and female participants (n = 10) ingested 4 preloaded drinks containing glucose (40 g), sucralose (60 mg), 3-O-methylglucose (40 g), or a tagatose/isomalt mixture (40 g) 15 minutes before consuming a labeled mashed potato meal containing 13C-octanoic acid. Sucralose had no effect on blood glucose, GLP-1, GIP, or insulin.57 In this trial, the addition of a control preloaded drink, such as water, as well as screening for past NNS use, would have been helpful for the interpretation of the findings. Wu et al58 examined the acute effect of NNSs on levels of blood glucose, plasma insulin, and GLP-1 in healthy men (n = 10) in a randomized, single-blinded, crossover trial. Participants consumed either water alone (240 mL) or a similar amount of water sweetened with sucralose (52 mg), acesulfame K (200 mg), or sucralose (46 mg) and acesulfame K (26 mg) after an overnight fast. An oral glucose tolerance test with 75 g of glucose and containing 13C-acetate (150 mg) was administered 10 minutes after each treatment. Prior to glucose ingestion, levels of blood glucose, plasma insulin, and GLP-1 did not change with any of the sweetened drinks or water, but all increased after the oral glucose tolerance test (P < 0.001 for each) and were similar among all treatment groups.58 Stellingwerff et al59 investigated the acute effect of sucralose ingestion on blood glucose and plasma insulin during exercise in a randomized, double-blinded, crossover study. Healthy male cyclists (n = 23) consumed eight 50-mL doses of either a 1mM (20 mg) sucralose solution or placebo (sucralose mouthwash followed by drinking 50 mL of water) every 15 minutes for 2 hours, starting 120 minutes before the beginning of exercise and followed by ingestion of a maltodextrin drink (34 g) over a 2-hour cycling period. Ingestion of sucralose had no effect on blood glucose or insulin levels.59 Sylvetsky et al61 investigated the acute metabolic effects of NNSs in diet sodas in a randomized crossover study. In study arm 1, healthy adults (n = 30) consumed 355 mL of water alone or water combined with different doses of preloaded sucralose (68 mg, 170 mg, and 250 mg). In study arm 2, adults (n = 31) consumed 355 mL of diet soda containing 18 mg of sucralose, 18 mg of acesulfame K, and 57 mg of aspartame; 355 mL of diet soda containing 68 mg of sucralose and 41 mg of acesulfame K; or 355 mL of carbonated water containing 68 mg of sucralose and 41 mg of acesulfame K in a randomized design. In study arm 1, the different doses of preloaded sucralose had no effect on glucose absorption or on levels of glucose, insulin, C-peptides, or the gut hormones GLP-1 and GIP. Carbonated water with NNSs, compared with carbonated water alone, also had no effect on the parameters measured. However, the results of study arm 2 showed that levels of the GLP-1 hormone were increased after diet soda intake, but not after carbonated water intake.61 These results are similar to those reported by Brown et al52 and may be attributable to the additional ingredients present in the diet soda, which can cause an increase in GLP-1 hormones. Only a few trials have demonstrated effects of a single dose of NNS consumption on glucose, insulin, insulin sensitivity, acute insulin response, or gut hormones. Brown et al41 examined the acute effects of diet soda on blood glucose, insulin, and gut hormones in young participants with T1DM (n = 9) or T2DM (n = 10) and in healthy volunteers (n = 25) in a randomized crossover study. Participants received 240 mL of diet soda containing sucralose (190 ± 38 mg/mL) and acesulfame K (108 ± 0.6 mg/mL) or 240 mL of carbonated water as placebo. After 10 minutes, an oral glucose tolerance test with a 75-g glucose load was performed. The results showed no difference in blood glucose, C-peptides, or GIP between the 2 conditions in all groups. However, the GLP-1 AUC was 43% higher after diet soda ingestion (P = 0.02) vs carbonated water ingestion in the patients with T1DM, but not in the patients with T2DM,41 and the GLP-1 AUC was 34% higher after diet soda consumption in healthy participants. These reported increases in the GLP-1 AUC are similar to results reported by Brown et al52 and Sylvetsky et al,61 which may be attributable to the presence of other ingredients in the diet soda. Past use of NNSs by the participants also might have affected the outcomes measured, but this was not reported in this study. Pepino et al44 examined the acute effect of sucralose consumption on glucose metabolism in participants who were morbidly obese (n = 17). In a randomized crossover trial, participants received either 60 mL of distilled water (control condition) or 60 mL of a sucralose solution (2 mmol/L; 48 mg sucralose) after an overnight fast. Following the treatments, an oral glucose tolerance test with a 75-g glucose load was performed. The results showed that peak values for glucose, C-peptides, insulin, the insulin AUC, and insulin secretion rates were higher following the oral glucose tolerance test in the sucralose group compared with the water group. Concentrations and AUCs of GLP-1, GIP, and glucagon in the water- and sucralose-treated groups were similar.44 Decreases in insulin sensitivity and insulin clearance of 23% ± 20% (P = 0.01) and 7% ± 4% (P = 0.04), respectively, were also reported. Temizkan et al60 assessed the acute metabolic effects of NNSs in healthy participants (n = 8) and patients newly diagnosed with T2DM (n = 8) but not on medication. In this randomized, single-blinded, crossover study, participants received sucralose (24 mg; tabletop formulation) or aspartame (72 mg; tabletop formulation) in 200 mL of water or water alone 15 minutes before an oral glucose tolerance test (75 g of glucose). The results showed that consumption of sucralose was associated with lower blood glucose and increased GLP-1 levels (as determined by total AUC) in the healthy participants, but there was no effect on insulin or C-peptide concentrations. In the patients with T2DM, the total AUCs were similar for blood glucose, insulin, C-peptides, and GLP-1 after treatment with sucralose and water.60 The tabletop sweeteners used in this study were commercial packets. This study did not control for other ingredients and fillers in the sweeteners, which could have mediated the effect on GLP-1. Studies evaluating the effect of repeated doses of aspartame on glucose metabolism The effect of repeated doses of aspartame has been assessed in healthy and diabetic individuals (Table 2). Nehrling et al64 conducted a randomized, double-blinded, placebo-controlled trial in participants with T1DM or T2DM (n = 62) to measure the effect of repeated daily consumption of aspartame on glucose and HbA1c. Study participants received either aspartame capsules (2.7 g) or placebo capsules containing corn starch (20 mg) every day with meals for 18 weeks. Concentrations of blood glucose and HbA1c were similar in both groups.64 However, the delivery of aspartame in capsule form might have resulted in the bypass of oral sweet taste receptors, and the presence of diabetes might have affected the outcomes measured. In a double-blinded crossover trial with two 6-week study periods, Colagiuri et al66 tested the effect of aspartame added to meals and beverages on levels of blood glucose and insulin in participants with controlled T2DM. Participants (n = 9) received aspartame (162 mg) during the aspartame period and sucrose (45 g) during the sucrose period. The results showed that aspartame did not cause changes in levels of glucose or HbA1c.66 However, T2DM might have affected these outcomes. Higgins et al74 assessed the effect of repeated daily doses of aspartame on glucose metabolism in a randomized parallel-arm trial. Healthy participants (n = 93) consumed different doses of aspartame (350 mg or 1050 mg) dissolved in 500 mL of beverage, once daily for 12 weeks. Both doses of aspartame resulted in similar concentrations of glucose, insulin, and the hormones GIP and GLP-1.74 Bonnet et al75 reported similar findings when they investigated the effects of aspartame and acesulfame K on insulin sensitivity and insulin secretion in a randomized, crossover, double-blinded study. Healthy men (n = 50) received 2 cans of a carbonated beverage (330 mL) containing aspartame (129 mg) and acesulfame K (13 mg) or an unsweetened carbonated beverage as a control, daily for 12 weeks. The results showed no significant differences in insulin sensitivity or secretion between the 2 groups.75 However, the generalizability of this study is limited because only male participants were included. Studies evaluating the effect of a single dose of aspartame on glucose metabolism The acute effects of single doses of aspartame have been assessed in healthy, obese, and diabetic participants (Table 2). Rodin67 conducted a randomized crossover trial to evaluate the acute effect of aspartame in overweight and normal-weight healthy participants (n = 24). Participants consumed aspartame (250 mg), fructose (50 g), or glucose (50 g) in 500 mL of water or water alone as a control. The results showed no effects of aspartame on blood concentrations of glucose, insulin, or glucagon.67 Härtel et al68 reported findings consistent with those of Rodin.67 In an RCT, they examined the acute effect of a single dose of aspartame on glucose and insulin levels in healthy adults (n = 14). Each participant received either 330 mL of water with aspartame (165 mg), sucrose (33 g), acesulfame K (165 mg), cyclamate (800 mg), or saccharin (75 mg). The results showed no effects of NNS consumption, when compared with sucrose consumption, on insulin or glucose concentrations.68 Anton et al69 tested the acute effect of preloaded NNSs on postprandial glucose and insulin concentrations in a crossover study. Healthy lean (n = 19) and obese (n = 12) participants received preloads containing tea sweetened with aspartame, sucrose, or stevia before meals. The results showed that plasma glucose concentrations were lower after stevia consumption than after aspartame or sucrose consumption (P < 0.01). Insulin concentrations were also lower with the stevia preload compared with the aspartame and sucrose preloads (P < 0.05).69 However, the exact concentrations of NNSs used in this trial were not reported, and the tea could have contained other ingredients that may have affected the outcomes measured. Maersk et al70 assessed the acute effect of NNSs on concentrations of glucose and incretin hormones in a crossover trial. Healthy participants with obesity (n = 24) received 500 mL of regular soft drink, skimmed milk, diet soft drink sweetened with aspartame, or water. The results showed no effect of the diet cola drink on glucose, insulin, GLP-1, GIP, or ghrelin.70 The concentrations of the NNSs in the diet cola drink were not reported. Olalde-Mendoza and Moreno-González71 measured the acute effect of diet soda on capillary blood glucose in patients with T2DM (n = 80). After an overnight fast, patients received either 200 mL of diet soda (containing 40 mg of aspartame and 100 g of acesulfame K) or 200 mL of regular soda. There was no effect of diet soda consumption on capillary blood glucose.71 However, diabetes may have played a role in these outcomes. Bryant et al72 examined the acute effect of aspartame on glycemic responses in a randomized crossover trial. Healthy participants (n = 10) were studied on 4 separate days. After an overnight fast, participants received glucose only (45 g), glucose (45 g) and aspartame (150 mg), glucose (45 g) and acesulfame K (85 mg), or glucose (45 g) and saccharin (20 mg) in 250 mL of water. The results showed that fasting blood glucose concentrations were similar for the different test conditions.72 Tey et al73 examined the acute effect of NNSs on 24-hour glucose profiles in a randomized, double-blinded, crossover study in which healthy men (n = 30) consumed one of the following treatments as beverages: aspartame (0.44 g) in 500 mL of water, monk fruit extract (0.63 g) in 500 mL of water, stevia (0.33 g) in 500 mL of water, or sucrose (65 g) in 500 mL of water. Treatments were masked with strawberry flavor and pink color. Glucose and insulin AUCs were similar in all groups.73 However, the generalizability of the results is limited to men, as only male participants were included. Only a few trials have shown the acute effects of a single dose of aspartame consumption. Horwitz et al65 carried out an open, randomized, crossover study to measure the acute effect of a single dose of NNSs in healthy women (n = 12) and patients with T2DM (n = 10) taking oral hypoglycemic medication. Participants were asked to drink 300 mL of cherry-flavored Kool-Aid sweetened with aspartame (400 mg) or saccharin (135 mg) after an overnight fast and to continue fasting throughout the 3-hour study period. The results showed no significant changes in plasma levels of glucose or insulin in any of the treatment groups. However, the mean insulin AUC was higher after aspartame consumption than after saccharin or control beverage consumption in the healthy participants.65 Moller45 determined the acute effects of single doses of aspartame on glucose and insulin levels in healthy participants (n = 10). During study visits, participants consumed aspartame (1 g) or bovine albumin (12.2 g) in 200 mL of water or water alone as a control. Glucose concentrations decreased after aspartame consumption compared with water consumption (P < 0.05), but insulin levels were not affected.45 Melanson et al,46 who examined the acute effect of aspartame on blood glucose concentrations in healthy participants (n = 10) in a crossover study, reported findings in agreement with those of Moller.45 In their study, participants consumed beverages containing aspartame, high fat, or simple carbohydrate, followed by ad libitum meals. Blood glucose concentrations decreased (P = 0.014) in 40% of the participants after aspartame consumption.46 Hall et al43 observed no increase in blood glucose levels when they investigated the acute effects of aspartame on glucose, insulin, and GLP-1 hormones in a crossover study. Healthy participants (n = 6) consumed capsules containing aspartame (400 mg), a combination of aspartic acid (176 mg) and phenylalanine (224 mg), or corn flour (400 mg), used as control. Aspartame plus the amino acids decreased plasma GLP-1 concentrations, while aspartame alone did not affect glucose, insulin, or GIP concentrations.43 CONCLUSION The evidence from the totality of clinical trials conducted to date (1969–2019) is insufficient to support adverse or beneficial effects of sucralose or aspartame consumption on glucose metabolism and gut hormones. The aim of this review was to provide a summary of RCTs that measured the effects of aspartame and sucralose on glucose metabolism and gut hormones. It is still unclear if repeated daily exposures or single exposures to aspartame or sucralose are associated with changes in glucose metabolism or gut hormones, primarily because of the many variations in and between the existing RCTs as well as the limitations of these studies. In particular, participants in future RCTs need to be screened for past NSS use to determine if they are nonconsumers or light consumers of NNSs and if they have a history of prolonged use or abstinence from NNSs. This is important because repeated NNS intake might affect glucose metabolism37 and could cause adaptation within the human gut microbiome. Other limitations include the failure to report or measure the concentrations of NNSs used in trials, which makes it difficult to determine if the dosage in a trial is applicable to real-life situations. This also makes it challenging to replicate the results in subsequent trials. Moreover, the routes of administration used varied widely, with some studies using intragastric or intraduodenal administration and others using oral capsules. Unusual routes of NNS administration that bypass the activation of oral sweet receptors might cause variations in the outcomes and do not reflect the normal intake of NNSs. Other ingredients present in the diet drinks or packets used also might interact with the NNSs. Since other ingredients could also inhibit or boost the potential adverse effects of the NNSs, it is important to control for these ingredients. Some trials also selected one sex, which limits the generalizability of their results. Variations in the microbial composition of the human gut might also affect each individual response to NNS consumption differently, resulting in variable results. Finally, some studies administered NNSs at intakes higher than would be consumed during a normal pattern of use. While it is difficult to design a perfect study, it is important to consider the limitations of RCTs when interpreting the results. In conclusion, few clinical trials have found any effects of aspartame or sucralose consumption on glucose metabolism (Table 341–75).However, the trials included in this review used varying methods and reported conflicting results, which makes comparisons difficult. For example, 1 study found higher glucose concentrations in morbidly obese participants after sucralose consumption, while 3 studies found lower glucose concentrations and 33 studies found no effect on glucose concentrations. Moreover, only 4 studies reported increased GLP-1 concentrations in participants who were healthy or who had T1DM. Three studies found that sucralose consumption decreased insulin sensitivity in healthy and morbidly obese participants, 1 study reported a decrease in the acute insulin response in healthy participants, and another trial reported an increase. However, studies that involved intragastric or intraduodenal administration of NNSs are consistent in their findings: sucralose consumption has no effect on glucose or insulin concentrations or on gut hormone secretion. Of the 16 studies that compared aspartame with either other NNSs or placebo, 2 reported a decrease in glucose concentrations following aspartame consumption and 1 reported a decrease in GLP-1 concentrations. Table 3 Effects of sucralose and aspartame consumption on glucose metabolism and gut hormones Reference . NNS used . Dosing frequency . Route of administration . Characteristics of participants . Effects on measures of glucose metabolism . . . . . . Blood glucose . Insulin . GLP-1 . GIP . Insulin sensitivity . Acute insulin response . Insulin clearance . HbA1c . C-peptides . Glucagon . Mezitis et al (1996)47 Sucralose Single dose Oral T1DM No effect No effect Sucralose Single dose Oral T2DM No effect No effect Ma et al (2009)51 Sucralose Single dose Intragastric Healthy No effect No effect No effect No effect Brown et al (2009)52 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Ma et al (2010)53 Sucralose Single dose Intraduodenal Healthy No effect No effect Brown et al (2011)54 Sucralose Single dose Oral Healthy No effect No effect No effect Steinert et al (2011)55 Sucralose Single dose Intragastric Healthy No effect No effect No effect Ford et al (2011)56 Sucralose Single dose Oral Healthy No effect No effect No effect Wu et al (2012)57 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Brown et al (2012)41 Sucralose Single dose Oral Healthy No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T1DM No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T2DM, obese No effect No effect No effect Wu et al (2013)58 Sucralose Single dose Oral Healthy No effect No effect No effect Stellingwerff et al (2013)59 Sucralose Single dose Oral Healthy No effect No effect Pepino et al (2013)44 Sucralose Single dose Oral Morbidly obese Increased (P < 0.004) Increased No effect No effect Decreased (P = 0.01) Decreased (P = 0.04) No effect Temizkan et al (2015)60a Sucralose Single dose Oral Healthy Decreased (P = 0.002) No effect Increased (P = 0.04) No effect Sucralose Single dose Oral T2DM No effect No effect No effect No effect Sylvetsky et al (2016)62 Sucralose Single dose Oral Healthy No effect No effect No effect No effect No effect Grotz et al (2017)62 Sucralose Repeated daily dose Oral Healthy No effect No effect No effect Romo-Romo et al (2018)63 Sucralose Repeated daily dose Oral Healthy No effect Decreased (P = 0.04) Increased (P = 0.04) Lertrit et al (2018)42 Sucralose Repeated daily dose Oral Healthy No effect Increased AUC (P < 0.001) Decreased (P < 0.005) Decreased (P < 0.005) Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Grotz et al (2003)49 Sucralose Repeated daily dose Oral T2DM, obese No effect No effect No effect No effect Reyna et al (2003)50 Sucralose Repeated daily dose Oral T2DM, obese No effect Decreased Horwitz et al (1988)65 Aspartame Single dose Oral Healthy No effect Mean AUC increased (P < 0.05) No effect Aspartame Single dose Oral T2DM No effect No effect No effect Rodin (1990)67 Aspartame Single dose Oral Healthy No effect No effect No effect Aspartame Single dose Oral Obese No effect No effect No effect Moller (1991)45 Aspartame Single dose Oral Healthy Decreased (P < 0.05) No effect Härtel et al (1993)68 Aspartame Single dose Oral Healthy No effect No effect Melanson et al (1999)46 Aspartame Single dose Oral Healthy Decreased by 40% Hall et al (2003)43 Aspartame Single dose Oral Healthy No effect No effect Decreased (P < 0.05) No effect Anton et al (2010)69 Aspartame Single dose Oral Healthy No effect No effect Aspartame Single dose Oral Obese No effect No effect Maersk et al (2012)70 Aspartame Single dose Oral Healthy, obese No effect No effect No effect No effect Olalde-Mendoza & Moreno-Gonzalez (2013)71 Aspartame Single dose Oral T2DM No effect Bryant et al (2014)72 Aspartame Single dose Oral Healthy No effect Temizkan et al (2015)60a Aspartame Single dose Oral Healthy No effect No effect No effect No effect Aspartame Single dose Oral T2DM No effect No effect No effect No effect Tey et al (2017)73 Aspartame Single dose Oral Healthy No effect No effect Nehrling et al (1985)64 Aspartame Repeated daily dose Oral T1DM No effect No effect Aspartame Repeated daily dose Oral T2DM No effect No effect Colagiuri et al (1989)66 Aspartame Repeated daily dose Oral T2DM No effect No effect Higgins et al (2018)74 Aspartame Repeated daily dose Oral Healthy No effect No effect No effect No effect Bonnet et al (2018)75 Aspartame Repeated daily dose Oral Healthy No effect No effect Reference . NNS used . Dosing frequency . Route of administration . Characteristics of participants . Effects on measures of glucose metabolism . . . . . . Blood glucose . Insulin . GLP-1 . GIP . Insulin sensitivity . Acute insulin response . Insulin clearance . HbA1c . C-peptides . Glucagon . Mezitis et al (1996)47 Sucralose Single dose Oral T1DM No effect No effect Sucralose Single dose Oral T2DM No effect No effect Ma et al (2009)51 Sucralose Single dose Intragastric Healthy No effect No effect No effect No effect Brown et al (2009)52 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Ma et al (2010)53 Sucralose Single dose Intraduodenal Healthy No effect No effect Brown et al (2011)54 Sucralose Single dose Oral Healthy No effect No effect No effect Steinert et al (2011)55 Sucralose Single dose Intragastric Healthy No effect No effect No effect Ford et al (2011)56 Sucralose Single dose Oral Healthy No effect No effect No effect Wu et al (2012)57 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Brown et al (2012)41 Sucralose Single dose Oral Healthy No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T1DM No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T2DM, obese No effect No effect No effect Wu et al (2013)58 Sucralose Single dose Oral Healthy No effect No effect No effect Stellingwerff et al (2013)59 Sucralose Single dose Oral Healthy No effect No effect Pepino et al (2013)44 Sucralose Single dose Oral Morbidly obese Increased (P < 0.004) Increased No effect No effect Decreased (P = 0.01) Decreased (P = 0.04) No effect Temizkan et al (2015)60a Sucralose Single dose Oral Healthy Decreased (P = 0.002) No effect Increased (P = 0.04) No effect Sucralose Single dose Oral T2DM No effect No effect No effect No effect Sylvetsky et al (2016)62 Sucralose Single dose Oral Healthy No effect No effect No effect No effect No effect Grotz et al (2017)62 Sucralose Repeated daily dose Oral Healthy No effect No effect No effect Romo-Romo et al (2018)63 Sucralose Repeated daily dose Oral Healthy No effect Decreased (P = 0.04) Increased (P = 0.04) Lertrit et al (2018)42 Sucralose Repeated daily dose Oral Healthy No effect Increased AUC (P < 0.001) Decreased (P < 0.005) Decreased (P < 0.005) Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Grotz et al (2003)49 Sucralose Repeated daily dose Oral T2DM, obese No effect No effect No effect No effect Reyna et al (2003)50 Sucralose Repeated daily dose Oral T2DM, obese No effect Decreased Horwitz et al (1988)65 Aspartame Single dose Oral Healthy No effect Mean AUC increased (P < 0.05) No effect Aspartame Single dose Oral T2DM No effect No effect No effect Rodin (1990)67 Aspartame Single dose Oral Healthy No effect No effect No effect Aspartame Single dose Oral Obese No effect No effect No effect Moller (1991)45 Aspartame Single dose Oral Healthy Decreased (P < 0.05) No effect Härtel et al (1993)68 Aspartame Single dose Oral Healthy No effect No effect Melanson et al (1999)46 Aspartame Single dose Oral Healthy Decreased by 40% Hall et al (2003)43 Aspartame Single dose Oral Healthy No effect No effect Decreased (P < 0.05) No effect Anton et al (2010)69 Aspartame Single dose Oral Healthy No effect No effect Aspartame Single dose Oral Obese No effect No effect Maersk et al (2012)70 Aspartame Single dose Oral Healthy, obese No effect No effect No effect No effect Olalde-Mendoza & Moreno-Gonzalez (2013)71 Aspartame Single dose Oral T2DM No effect Bryant et al (2014)72 Aspartame Single dose Oral Healthy No effect Temizkan et al (2015)60a Aspartame Single dose Oral Healthy No effect No effect No effect No effect Aspartame Single dose Oral T2DM No effect No effect No effect No effect Tey et al (2017)73 Aspartame Single dose Oral Healthy No effect No effect Nehrling et al (1985)64 Aspartame Repeated daily dose Oral T1DM No effect No effect Aspartame Repeated daily dose Oral T2DM No effect No effect Colagiuri et al (1989)66 Aspartame Repeated daily dose Oral T2DM No effect No effect Higgins et al (2018)74 Aspartame Repeated daily dose Oral Healthy No effect No effect No effect No effect Bonnet et al (2018)75 Aspartame Repeated daily dose Oral Healthy No effect No effect a Study tested both aspartame and sucralose. Abbreviations: AUC, area under the curve; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like protein 1; HbA1c, hemoglobin A1c; T1DM, type 1 diabetes mellitus, T2DM, type 2 diabetes mellitus. Open in new tab Table 3 Effects of sucralose and aspartame consumption on glucose metabolism and gut hormones Reference . NNS used . Dosing frequency . Route of administration . Characteristics of participants . Effects on measures of glucose metabolism . . . . . . Blood glucose . Insulin . GLP-1 . GIP . Insulin sensitivity . Acute insulin response . Insulin clearance . HbA1c . C-peptides . Glucagon . Mezitis et al (1996)47 Sucralose Single dose Oral T1DM No effect No effect Sucralose Single dose Oral T2DM No effect No effect Ma et al (2009)51 Sucralose Single dose Intragastric Healthy No effect No effect No effect No effect Brown et al (2009)52 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Ma et al (2010)53 Sucralose Single dose Intraduodenal Healthy No effect No effect Brown et al (2011)54 Sucralose Single dose Oral Healthy No effect No effect No effect Steinert et al (2011)55 Sucralose Single dose Intragastric Healthy No effect No effect No effect Ford et al (2011)56 Sucralose Single dose Oral Healthy No effect No effect No effect Wu et al (2012)57 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Brown et al (2012)41 Sucralose Single dose Oral Healthy No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T1DM No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T2DM, obese No effect No effect No effect Wu et al (2013)58 Sucralose Single dose Oral Healthy No effect No effect No effect Stellingwerff et al (2013)59 Sucralose Single dose Oral Healthy No effect No effect Pepino et al (2013)44 Sucralose Single dose Oral Morbidly obese Increased (P < 0.004) Increased No effect No effect Decreased (P = 0.01) Decreased (P = 0.04) No effect Temizkan et al (2015)60a Sucralose Single dose Oral Healthy Decreased (P = 0.002) No effect Increased (P = 0.04) No effect Sucralose Single dose Oral T2DM No effect No effect No effect No effect Sylvetsky et al (2016)62 Sucralose Single dose Oral Healthy No effect No effect No effect No effect No effect Grotz et al (2017)62 Sucralose Repeated daily dose Oral Healthy No effect No effect No effect Romo-Romo et al (2018)63 Sucralose Repeated daily dose Oral Healthy No effect Decreased (P = 0.04) Increased (P = 0.04) Lertrit et al (2018)42 Sucralose Repeated daily dose Oral Healthy No effect Increased AUC (P < 0.001) Decreased (P < 0.005) Decreased (P < 0.005) Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Grotz et al (2003)49 Sucralose Repeated daily dose Oral T2DM, obese No effect No effect No effect No effect Reyna et al (2003)50 Sucralose Repeated daily dose Oral T2DM, obese No effect Decreased Horwitz et al (1988)65 Aspartame Single dose Oral Healthy No effect Mean AUC increased (P < 0.05) No effect Aspartame Single dose Oral T2DM No effect No effect No effect Rodin (1990)67 Aspartame Single dose Oral Healthy No effect No effect No effect Aspartame Single dose Oral Obese No effect No effect No effect Moller (1991)45 Aspartame Single dose Oral Healthy Decreased (P < 0.05) No effect Härtel et al (1993)68 Aspartame Single dose Oral Healthy No effect No effect Melanson et al (1999)46 Aspartame Single dose Oral Healthy Decreased by 40% Hall et al (2003)43 Aspartame Single dose Oral Healthy No effect No effect Decreased (P < 0.05) No effect Anton et al (2010)69 Aspartame Single dose Oral Healthy No effect No effect Aspartame Single dose Oral Obese No effect No effect Maersk et al (2012)70 Aspartame Single dose Oral Healthy, obese No effect No effect No effect No effect Olalde-Mendoza & Moreno-Gonzalez (2013)71 Aspartame Single dose Oral T2DM No effect Bryant et al (2014)72 Aspartame Single dose Oral Healthy No effect Temizkan et al (2015)60a Aspartame Single dose Oral Healthy No effect No effect No effect No effect Aspartame Single dose Oral T2DM No effect No effect No effect No effect Tey et al (2017)73 Aspartame Single dose Oral Healthy No effect No effect Nehrling et al (1985)64 Aspartame Repeated daily dose Oral T1DM No effect No effect Aspartame Repeated daily dose Oral T2DM No effect No effect Colagiuri et al (1989)66 Aspartame Repeated daily dose Oral T2DM No effect No effect Higgins et al (2018)74 Aspartame Repeated daily dose Oral Healthy No effect No effect No effect No effect Bonnet et al (2018)75 Aspartame Repeated daily dose Oral Healthy No effect No effect Reference . NNS used . Dosing frequency . Route of administration . Characteristics of participants . Effects on measures of glucose metabolism . . . . . . Blood glucose . Insulin . GLP-1 . GIP . Insulin sensitivity . Acute insulin response . Insulin clearance . HbA1c . C-peptides . Glucagon . Mezitis et al (1996)47 Sucralose Single dose Oral T1DM No effect No effect Sucralose Single dose Oral T2DM No effect No effect Ma et al (2009)51 Sucralose Single dose Intragastric Healthy No effect No effect No effect No effect Brown et al (2009)52 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Ma et al (2010)53 Sucralose Single dose Intraduodenal Healthy No effect No effect Brown et al (2011)54 Sucralose Single dose Oral Healthy No effect No effect No effect Steinert et al (2011)55 Sucralose Single dose Intragastric Healthy No effect No effect No effect Ford et al (2011)56 Sucralose Single dose Oral Healthy No effect No effect No effect Wu et al (2012)57 Sucralose Single dose Oral Healthy No effect No effect No effect No effect Brown et al (2012)41 Sucralose Single dose Oral Healthy No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T1DM No effect Increased (P = 0.02) No effect Sucralose Single dose Oral T2DM, obese No effect No effect No effect Wu et al (2013)58 Sucralose Single dose Oral Healthy No effect No effect No effect Stellingwerff et al (2013)59 Sucralose Single dose Oral Healthy No effect No effect Pepino et al (2013)44 Sucralose Single dose Oral Morbidly obese Increased (P < 0.004) Increased No effect No effect Decreased (P = 0.01) Decreased (P = 0.04) No effect Temizkan et al (2015)60a Sucralose Single dose Oral Healthy Decreased (P = 0.002) No effect Increased (P = 0.04) No effect Sucralose Single dose Oral T2DM No effect No effect No effect No effect Sylvetsky et al (2016)62 Sucralose Single dose Oral Healthy No effect No effect No effect No effect No effect Grotz et al (2017)62 Sucralose Repeated daily dose Oral Healthy No effect No effect No effect Romo-Romo et al (2018)63 Sucralose Repeated daily dose Oral Healthy No effect Decreased (P = 0.04) Increased (P = 0.04) Lertrit et al (2018)42 Sucralose Repeated daily dose Oral Healthy No effect Increased AUC (P < 0.001) Decreased (P < 0.005) Decreased (P < 0.005) Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Baird et al (2000)48 Sucralose Repeated daily dose Oral Healthy No effect No effect Grotz et al (2003)49 Sucralose Repeated daily dose Oral T2DM, obese No effect No effect No effect No effect Reyna et al (2003)50 Sucralose Repeated daily dose Oral T2DM, obese No effect Decreased Horwitz et al (1988)65 Aspartame Single dose Oral Healthy No effect Mean AUC increased (P < 0.05) No effect Aspartame Single dose Oral T2DM No effect No effect No effect Rodin (1990)67 Aspartame Single dose Oral Healthy No effect No effect No effect Aspartame Single dose Oral Obese No effect No effect No effect Moller (1991)45 Aspartame Single dose Oral Healthy Decreased (P < 0.05) No effect Härtel et al (1993)68 Aspartame Single dose Oral Healthy No effect No effect Melanson et al (1999)46 Aspartame Single dose Oral Healthy Decreased by 40% Hall et al (2003)43 Aspartame Single dose Oral Healthy No effect No effect Decreased (P < 0.05) No effect Anton et al (2010)69 Aspartame Single dose Oral Healthy No effect No effect Aspartame Single dose Oral Obese No effect No effect Maersk et al (2012)70 Aspartame Single dose Oral Healthy, obese No effect No effect No effect No effect Olalde-Mendoza & Moreno-Gonzalez (2013)71 Aspartame Single dose Oral T2DM No effect Bryant et al (2014)72 Aspartame Single dose Oral Healthy No effect Temizkan et al (2015)60a Aspartame Single dose Oral Healthy No effect No effect No effect No effect Aspartame Single dose Oral T2DM No effect No effect No effect No effect Tey et al (2017)73 Aspartame Single dose Oral Healthy No effect No effect Nehrling et al (1985)64 Aspartame Repeated daily dose Oral T1DM No effect No effect Aspartame Repeated daily dose Oral T2DM No effect No effect Colagiuri et al (1989)66 Aspartame Repeated daily dose Oral T2DM No effect No effect Higgins et al (2018)74 Aspartame Repeated daily dose Oral Healthy No effect No effect No effect No effect Bonnet et al (2018)75 Aspartame Repeated daily dose Oral Healthy No effect No effect a Study tested both aspartame and sucralose. Abbreviations: AUC, area under the curve; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like protein 1; HbA1c, hemoglobin A1c; T1DM, type 1 diabetes mellitus, T2DM, type 2 diabetes mellitus. Open in new tab Finally, it is clear from the limitations of the available RCTs that more clinical trials are required. In particular, future trials should consider the following: (1) the measurement of previous NNS exposure or incidental concomitant NNS exposure, as contamination of control groups or treatment groups is likely with the increased use of NNSs; (2) the route of NNS administration, ie, avoiding delivery routes such as capsules, which bypass oral taste receptor activation and the cephalic phase insulin response and do not replicate the usual route of NNS consumption, (3) the concentration of NNSs used, ie, ensuring that doses used are relevant to real-life intakes; (4) the study population, ie, ensuring that healthy and nonhealthy participants are included, (5) the use of an appropriate study design, especially with regard to controls and statistical power; and (6) the study duration, ie, including the use of longer intervention periods to investigate possible consequences of NNS consumption that occur only after long-term exposure to NNSs. Acknowledgments Author contributions. S.Y.A. created and executed the literature search, provided input on the literature tables, and wrote the manuscript. J.K.F. and D.S.M. contributed significantly to the improvement of the manuscript. All authors read, made critical revisions to, and approved the final manuscript. Funding/support. S.Y.A. was supported by the Kuwait Civil Service and Institute for Medical Specialization and the Ministry of Health of Kuwait. The funding agencies had no role in the writing of the manuscript or in the decision to submit the manuscript for publication. This manuscript did not undergo peer review by the external funding agency. The authors received no funding or benefits from industry or elsewhere to write this manuscript. Declaration of interest. 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TI - Effect of sucralose and aspartame on glucose metabolism and gut hormones
JF - Nutrition Reviews
DO - 10.1093/nutrit/nuz099
DA - 2020-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/effect-of-sucralose-and-aspartame-on-glucose-metabolism-and-gut-U07sclemRK
DP - DeepDyve
ER -