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Background: Substituting sweeteners with non-nutritive sweeteners (NNS) may aid in glycaemic control and body weight management. Limited studies have investigated energy compensation, glycaemic and insulinaemic responses to artificial and natural NNS. Objectives: This study compared the effects of consuming NNS (artificial versus natural) and sucrose (65 g) on energy intake, blood glucose and insulin responses. Methods: Thirty healthy male subjects took part in this randomised, crossover study with four treatments: aspartame-, monk fruit-, stevia- and sucrose-sweetened beverages. On each test day, participants were asked to consume a standardised breakfast in the morning, and they were provided with test beverage as a preload in mid-morning and ad libitum lunch was provided an hour after test beverage consumption. Blood glucose and insulin concentrations were measured every 15 min within the first hour of preload consumption and every 30 min for the subsequent 2 h. Participants left the study site 3 h after preload consumption and completed a food diary for the rest of the day. Results: Ad libitum lunch intake was significantly higher for the NNS treatments compared with sucrose ( P =0.010). The energy 'saved' from replacing sucrose with NNS was fully compensated for at subsequent meals; hence, no difference in total daily energy intake was found between the treatments ( P =0.831). The sucrose-sweetened beverage led to large spikes in blood glucose and insulin responses within the first hour, whereas these responses were higher for all three NNS beverages following the test lunch. Thus, there were no differences in total area under the curve (AUC) for glucose ( P =0.960) and insulin ( P =0.216) over 3 h between the four test beverages. Conclusions: The consumption of calorie-free beverages sweetened with artificial and natural NNS have minimal influences on total daily energy intake, postprandial glucose and insulin compared with a sucrose-sweetened beverage.

Adverse effects of hypercaloric, high-fructose diets on insulin sensitivity and lipids in human subjects have been shown repeatedly. The implications of fructose in amounts close to usual daily consumption, however, have not been well studied. This study assessed the effect of moderate amounts of fructose and sucrose compared with glucose on glucose and lipid metabolism. Nine healthy, normal-weight male volunteers (aged 21-25 years) were studied in this double-blind, randomized, cross-over trial. All subjects consumed four different sweetened beverages (600 mL/day) for 3 weeks each: medium fructose (MF) at 40 g/day, and high fructose (HF), high glucose (HG), and high sucrose (HS) each at 80 g/day. Euglycemic-hyperinsulinemic clamps with [6,6]-(2)H(2) glucose labeling were used to measure endogenous glucose production. Lipid profile, glucose, and insulin were measured in fasting samples. Hepatic suppression of glucose production during the clamp was significantly lower after HF (59.4 ± 11.0%) than HG (70.3 ± 10.5%, P < 0.05), whereas fasting glucose, insulin, and C-peptide did not differ between the interventions. Compared with HG, LDL cholesterol and total cholesterol were significantly higher after MF, HF, and HS, and free fatty acids were significantly increased after MF, but not after the two other interventions (P < 0.05). Subjects' energy intake during the interventions did not differ significantly from baseline intake. This study clearly shows that moderate amounts of fructose and sucrose significantly alter hepatic insulin sensitivity and lipid metabolism compared with similar amounts of glucose.

In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250 ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy-d-glucose. Glucose stimulated GLP-1 (P = 0·002) and peptide tyrosine tyrosine (PYY; P = 0·046) secretion and reduced fasting plasma ghrelin (P = 0·046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucose.

•Consumption of water sweetened with low- or no-calorie sweeteners (LNCS; saccharine, sucralose, or aspartame+acesulfame-K) over 4 wk had no significant effect on glycemic response in healthy women.•Insulin sensitivity did not change after regular LNCS consumption.•Lower glucagon-like peptide-1 secretion was found in the sucralose and aspartame+acesulfame-K groups at week 4. However, when compared with the control group, there were no differences between groups.•Body weight and composition did not change after LNCS consumption in daily-life doses. The aim of this study was to determine the effects of regular exposure to certain low- or no-calorie sweeteners (LNCS) on glucose tolerance and glucagon-like peptide 1 (GLP-1) release in healthy individuals. It was designed as a randomized, single-blinded, controlled study. Healthy and normoglycemic adults who did not have regular consumption of LNCS were recruited. Participants underwent a 75-g oral glucose tolerance test (OGTT) at baseline and were randomly assigned to consume 330 mL water sweetened with saccharine, sucralose, or aspartame + acesulfame-K (Asp+Ace-K), or plain water for the control group, daily for 4 wk. Fasting plasma glucose, insulin, GLP-1, and glycated hemoglobin A1c (HbA1c) levels and 1-h, 2-h, and 3-h plasma glucose and insulin levels during OGTT were obtained at baseline. The change in insulin sensitivity was assessed by both the Homeostatic Model Assessment Insulin Resistance (HOMA-IR) Index and the Matsuda Index. Anthropometric measurements and dietary intakes were determined at baseline. Baseline measurements were repeated at week 4. Of the participants enrolled in the study, 42 (age, 21.24 ± 2.26 y; body mass index, 20.65 ± 2.88 kg/m2) completed the 4-wk intervention period. There were no differences for glucose, insulin, GLP-1, or HbA1c levels or HOMA-IR scores at baseline or at week 4 when compared with the control group. The area under the curve of mean glucose and insulin values during OGTT were also found to be similar between groups at baseline and week 4. There were also no effects of LNCS intake on body weight, body composition, and waist circumference. These results suggest that regular consumption of LNCS-sweetened water similar to doses consumed in daily life over 4 wk had no significant effect on glycemic response, insulin sensitivity, GLP-1 release, and body weight in healthy individuals. This trial was registered at www.clinicaltrials.gov as NCT04904133.

Background/Objectives: Xylitol, a natural low-caloric bulk sweetener, is increasingly used as a sugar alternative due to its low-glycemic and low-insulinemic properties. The aim was to investigate the effect of orally administered xylitol, sucrose, and acesulfame potassium (ace-K) on energy intake during a subsequent ad libitum test meal. Methods: In this randomized, controlled, double-blind, crossover trial (ClinicalTrials.gov NCT05671965, 20 December 2022), we included 20 healthy participants with normal body weight. Over four study visits, participants consumed an oral preload containing 33.5 g xylitol, 33.5 g sucrose, or 0.1675 g ace-K dissolved in 300 mL water, or 300 mL pure water as control. Participants were provided with an ad libitum test meal 15 min after the preload consumption, and both energy intake and total energy intake (= preload + ad libitum test meal) were assessed. Blood samples were collected to quantify cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), glucose, and insulin concentrations. Results: Total energy intake was lower in response to xylitol and ace-K compared to sucrose (pTukey < 0.03), with no differences between xylitol and ace-K or water. Plasma CCK concentrations were higher in response to xylitol compared to sucrose, ace-K, and water (pHolm < 0.01), whereas GLP-1 concentrations did not differ between the preloads. Plasma glucose and insulin concentrations were lower in response to xylitol compared to sucrose (pHolm < 0.01), but xylitol led to an increase in insulin compared to ace-K and water (pHolm < 0.01). Conclusions: The consumption of oral preloads sweetened with xylitol or ace-K prior to an ad libitum test meal result in a lower total energy intake compared to a preload with sucrose.

To identify molecules that could enhance sweetness perception, we undertook the screening of a compound library using a cell-based assay for the human sweet taste receptor and a panel of selected sweeteners. In one of these screens we found a hit, SE-1, which significantly enhanced the activity of sucralose in the assay. At 50 μM, SE-1 increased the sucralose potency by >20-fold. On the other hand, SE-1 exhibited little or no agonist activity on its own. SE-1 effects were strikingly selective for sucralose. Other popular sweeteners such as aspartame, cyclamate, and saccharin were not enhanced by SE-1 whereas sucrose and neotame potency were increased only by 1.3- to 2.5-fold at 50 μM. Further assay-guided chemical optimization of the initial hit SE-1 led to the discovery of SE-2 and SE-3, selective enhancers of sucralose and sucrose, respectively. SE-2 (50 μM) and SE-3 (200 μM) increased sucralose and sucrose potencies in the assay by 24- and 4.7-fold, respectively. In human taste tests, 100 μM of SE-1 and SE-2 allowed for a reduction of 50% to >80% in the concentration of sucralose, respectively, while maintaining the sweetness intensity, and 100 μM SE-3 allowed for a reduction of 33% in the concentration of sucrose while maintaining the sweetness intensity. These enhancers did not exhibit any sweetness when tasted on their own. Positive allosteric modulators of the human sweet taste receptor could help reduce the caloric content in food and beverages while maintaining the desired taste.

The use of non-nutritive sweeteners (NNSs) as an alternative to caloric sugars has increased in recent years. Stevia is an NNS that has demonstrated beneficial effects on appetite and energy intake. However, the impact on the gut microbiota is not well understood. Therefore, we investigated how regular consumption of stevia, for up to 12 weeks, impacts the human gut microbiota. Healthy subjects with a normal body mass index participated in our study; the stevia group (n = 14) was asked to consume five drops of stevia twice daily, compared to control participants (n = 13). Faecal samples collected before and after treatment were analysed by 16S rRNA gene sequencing. Stevia did not cause significant changes in the alpha or beta diversity when compared to the control groups. When the relative abundances of taxa were investigated, no clear differences were detected. Conversely, a random forest analysis correctly associated the gut microbiome with the control and stevia groups with an average of 75% accuracy, suggesting that there are intrinsic patterns that could discriminate between control and stevia use. However, large-scale changes in the gut microbiota were not apparent in this study, and, therefore, our data suggest that stevia does not significantly impact the gut microbiota.

Background/objective: Artificial sweeteners were thought to be metabolically inactive, but after demonstrating that the gustatory mechanism was also localized in the small intestine, suspicions about the metabolic effects of artificial sweeteners have emerged. The objective of this study was to determine the effect of artificial sweeteners (aspartame and sucralose) on blood glucose, insulin, c-peptide and glucagon-like peptide-1 (GLP-1) levels. Subjects/methods: Eight newly diagnosed drug-naive type 2 diabetic patients (mean age 51.5±9.2 years; F/M: 4/4) and eight healthy subjects (mean age 45.0±4.1 years; F/M: 4/4) underwent 75 g oral glucose tolerance test (OGTT). During OGTT, glucose, insulin, c-peptide and GLP-1 were measured at 15- min intervals for 120 min. The OGTTs were performed at three settings on different days, where subjects were given 72 mg of aspartame and 24 mg of sucralose in 200 ml of water or 200 ml of water alone 15 min before OGTT in a single-blinded randomized order. Results: In healthy subjects, the total area under the curve (AUC) of glucose was statistically significantly lower in the sucralose setting than in the water setting ( P =0.002). There was no difference between the aspartame setting and the water setting ( P =0.53). Total AUC of insulin and c-peptide was similar in aspartame, sucralose and water settings. Total AUC of GLP-1 was significantly higher in the sucralose setting than in the water setting ( P =0.04). Total AUC values of glucose, insulin, c-peptide and GLP-1 were not statistically different in three settings in type 2 diabetic patients. Conclusions: Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in newly diagnosed type 2 diabetic patients.

•Glucose elicits an immediate deactivation of the hypothalamus.•Sucrose and fructose elicit a delayed deactivation of the hypothalamus•The non-caloric sweetener sucralose elicits a transient hypothalamic response•In the ventral tegmental area, sucralose elicits a very similar activation to plain water ingestion•The natural sugars appeared to only elicit a transient, if any, increase in ventral tegmental area activity The brain is essential in regulating intake of food and beverages by balancing energy homeostasis, which is regulated by the hypothalamus, with reward perception, which is regulated by the ventral tegmental area (VTA). The aim of this study was to investigate the effects of ingestion of glucose, fructose, sucrose, and sucralose (a non-caloric artificial sweetener) on the magnitude and trajectory of the hypothalamic and the VTA blood oxygen level–dependent (BOLD) responses. In five visits, 16 healthy men between 18 to 25 y of age with a body mass index between 20 and 23 kg/m2 drank five interventions in a randomized order while a functional magnetic resonance imaging scan was taken. The interventions consisted of 50 g of glucose, fructose, or sucrose, or 0.33 g of sucralose dissolved in 300 mL tap water. The control condition consisted of 300 mL of plain tap water. BOLD signals were determined in the hypothalamus and the VTA within a manually drawn region of interest. Differences in changes in BOLD signal between stimuli were analyzed using mixed models. Compared with the control condition, a decrease in BOLD signal in the hypothalamus was found after ingestion of glucose (P = 0.0003), and a lesser but delayed BOLD response was found after ingestion of sucrose (P = 0.006) and fructose (P = 0.003). Sucralose led to a smaller and transient response from the hypothalamus (P = 0.026). In the VTA, sucralose led to a very similar response to the water control condition, leading to an increase in VTA BOLD activity that continued over the measured time period. The natural sugars appeared to only lead to a transient increase in VTA activity. Glucose induces a deactivation in the hypothalamus immediately after ingestion and continued over the next 12 min, which is correlated with satiety signaling by the brain. Fructose and sucrose are both associated with a delayed and lesser response from the hypothalamus, likely because the sugars first have to be metabolized by the body. Sucralose leads to the smallest and most transient decrease in BOLD in the hypothalamus and leads to a similar response as plain water in the VTA, which indicates that sucralose might not have a similar satiating effect on the brain as the natural sugars.

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.