Almanac A1C

The Hidden Metabolic Trap: How Sucralose and Carbohydrates Together Disrupt Insulin Sensitivity and Glucose Control

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Introduction

The global rise in metabolic disease such as obesity and type 2 diabetes has driven a surge in the use of non-nutritive sweeteners (NNS) as alternatives to caloric sugars in food and beverages, sucralose, a chlorinated derivative of sucrose, stands out for its intense sweetness and widespread incorporation into diet products marketed for weight management and glycemic control. While regulatory approval of sucralose has largely been based on its minimal systematic absorption and presumed metabolic inertness, a growing body of research calls for a nuanced appraisal of its physiological effects, particularly in varied dietary contexts.

Traditional perspectives suggest that sucralose, when consumed alone, exerts negligible effects on glucose metabolism and insulin dynamics. However, recent studies indicate that its metabolic impact may be significantly altered when ingested concurrently with carbohydrates. The interplay between sucralose, sweet taste receptor activation, and nutrient sensing pathways appears to modulate glucose absorption and insulin signalling in ways that challenge the notion of NNS as metabolically neutral agents. This evolving evidence is of particular relevance to preventive medicine, nutrition counselling, and public health policy, where recommendations for sugar alternatives are commonplace.

This review critically examines the differential metabolic effects of sucralose depending on its consumption with or without carbohydrates. By exploring current mechanistic insights, human and animal studies, neuroendocrine and microbiome responses, and clinical implications, we seek to clarify sucralose’s role in metabolic disease prevention and provide guidance for safe and effective dietary strategies in both clinical and public health arenas.

Biochemical Properties and Mechanism of Action

Sucralose is a synthetic, high-intensity non-nutritive sweetener derived through the selective chlorination of sucrose. Its systematic chemical name is 1,6-dichloro-1,6dideoxy-b-D-fructofuranosyl-4-chloro-4-deoxy-a-D-galactopyranoside, through it is also referred to as trichlorogalactosucrose. The chemical formula of sucralose is C12H19CI3O8, with a molecular weight OF 397.63 g/mol. During the synthesis process, three hydroxyl (-OH) groups on the sucrose molecule are strategically replaced with chlorine atoms at positions 4,1’, and 6’, fundamentally altering its molecular structure and rendering it resistant to enzymatic hydrolysis by human digestive enzymes [1,2,3].

The clorination process confers sucralose with remarkable sweetness intensity, estimated to be approximately 600 times sweeter than sucrose, although this potency may vary depending on factors such as concentration, pH, temperature, and the presence of other ingredients. The substitution of chlorine for hydroxyl groups not only amplifies sweetness but also prevents the molecule from being metabolized as a source of energy, thereby conferring its non-nutritive status. Sucralose is a white, odourless, crystalline powder that is readily soluble in water, methanol, and ethanol, and exhibits stability across a wide range of temperatures and pH levels [2,3,4,5].

A distinctive pharmacokinetic feature of sucralose is its minimal absorption from the gastrointestinal tract. Human studies have consistently demonstrated that only 11-27% of ingested sucralose is absorbed from the gut, with the majority (approximately 73-89%) excreted unchanged in the feces. Of the absorbed fraction, most is rapidly excreted unchanged in the urine, with minor glucuronide conjugates representing only 2-3% of total oral intake. This limited bioavailability and lack of significant metabolism contribute to the widespread regulatory acceptance of sucralose as a safe, non-caloric sweetener [6,7,8,9,10,11,12].

Despite its poor systemic absorption, sucralose exerts notable physiological effects through its interaction with sweet taste receptors present in both the oral cavity and the gastrointestinal tract. These receptors, known as T1R2 and T1R3, heterodimerize to form the functional sweet taste receptor complex (T1R2 +T1R3), which is expressed not only on taste buds of the tongue but also enteroendocrine cells lining the intestinal epithelium. Upon binding to T1R2+T1R3 receptors, sucralose activates a G-protein-coupled signalling cascade involving a-gustducin, phospholipase C-b2 (PLC-b2), and transient receptor potential melastatin 5 (TRPM5). This activation triggers the release of incretin hormones, particularly glucagon like peptide-1 (GLP1), and glucose-dependent insulinotropic peptide (GIP), from enteroendocrine L-cells and K-cells, respectively [3,4,13,14,15,16].

Critically, studies in rodents have shown that sucralose can upregulate the expression of intestinal glucose transporters, specifically sodium-glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2), in a sweet taste receptor dependent manner. This upregulation enhances intestinal glucose absorption capacity and may alter postprandial glucose dynamics, particularly when sucralose is consumed in combination with carbohydrates. However, acute human studies have yielded inconsistent results, with some demonstrating no effect of intraduodenal sucralose on glucose absorption or incretin secretion when administered independently. These discrepancies highlight potential species differences in the expression and functionality of intestinal glucose transporters and sweet taste receptors, as well as the importance of nutritional context in determining sucralose’s metabolic impact [4,9,16,17,18,19].

Metabolic Impact of Sucralose Alone

When consumed in isolation, that is without concurrent carbohydrate ingestion, sucralose appears to exert minimal acute effects on glucose homeostasis, insulin secretion, and glycemic response in most healthy individuals. This observation is supported by a substantial body of evidence from both short-term and long-term randomized controlled trials, which collectively suggest that sucralose, when ingested independently, may be metabolically neutral or have only modest physiological effects.

Several well-controlled acute studies have demonstrated that sucralose consumption alone does not trigger significant changes in blood glucose or insulin levels. For instance, a randomized crossover study by Smeets and colleagues found no cephalic phase insulin response upon oral exposure to sucralose in healthy individuals, contrasting sharply with the early insulin rise observed when tasting glucose. Similarly, intraduodenal administration of sucralose without accompanying nutrients has failed to stimulate incretin or alter glucose absorption, reinforcing the concept that the metabolic effect of sucralose are largely nutrient dependent. These findings suggest that sweet taste receptor activation by sucralose in the absence of caloric substrates is insufficient to provoke clinically meaningful metabolic responses [19,20,21].

A pivotal study by Dalenberg et al. provides compelling evidence for the metabolic neutrality of sucralose when consumed alone. In this randomized parallel group trial involving healthy adults, participants who consumed seven sucralose sweetened beverages (without carbohydrates) over a 10-day period exhibited no changes in insulin sensitivity, glucose metabolism, or brain responses to sweet taste. This finding stands in stark contrast to the impaired glucose metabolism observed when sucralose was co-ingested with maltodextrin, underscoring the critical role of nutritional context in determining sucralose’s metabolic impact. Similarly, consuming the carbohydrate maltodextrin alone did not produce adverse effects, further supporting the hypothesis that the combination of sucralose with carbohydrates, rather than sucralose per se, drives metabolic dysregulation [22].

Long-term evidence from a 12-week, double-blind, randomized controlled trial conducted by Grotz and colleagues also supports the metabolic neutrality of sucralose when consumed independently. In this study, 47 normoglycemic male volunteers ingested approximately 333.3 mg of encapsulated sucralose three times daily at mealtimes for 12 weeks. Throughout the study period, no statistically significant differences were observed between the sucralose and placebo groups in fasting glucose, insulin, C-peptide, or glycated hemoglobin (HbA1c) levels. Oral glucose tolerance tests conducted at multiple time points during the intervention phase revealed no clinically meaningful differences in glucose, insulin, or C-peptide area under the curve (AUC) or time to peak levels between groups. The authors concluded that the collective evidence supports the notion that daily consumption of sucralose has no effect on glycemic control in healthy individuals [23].

Similarly, a 12-week randomized controlled trial in Asian Indians with type 2 diabetes, in which sucralose replaced sucrose in coffee or tea (approximately 60cal of added sugar), reported no changes in HbA1c, fasting plasma glucose, lipid profile, or inflammatory markers compared to controls who continued consuming sucrose. While small reductions in body weight, body mass index, and waist circumference were observed in sucralose group, glycemic parameters remained unaffected, suggesting that sucralose does not adversely influence glucose metabolism when used as a sugar substitute in beverages consumed independently of carbohydrate rich meals [24].

However, it is important to note that not all studies support the metabolic neutrality of sucralose when consumed alone. A randomized controlled trial by Romo-Romo et al. involving 33 healthy young adults with low habitual consumption of non-nutritive sweeteners demonstrated that daily ingestion of. Sucralose at 15% of the acceptable daily intake (ADI) for 14 days resulted in a statistically significant 17.7% decrease in insulin sensitivity, as measured by modified intravenous glucose tolerance tests. Additionally, participants with adequate adherence to intervention showed increased acute insulin response to glucose. These findings suggest that even in the absence of exogenous carbohydrate co-ingestion, sucralose may exert subtle effects on insulin dynamics in certain populations, particularly individuals who are not habitual users of non-nutritive sweeteners [25].

Chronic sucralose consumption has also been associated with modest metabolic perturbations in some populations. A study by Mendoza-Jiménez and colleagues reported that healthy young adults consuming 48 mg sucralose daily for 10 weeks exhibited elevated fasting insulin levels and reduced insulin sensitivity (as indicated by a decreased Matsuda index) during oral glucose tolerance tests, despite no significant changes in fasting glucose. Interestingly, these effects were not observed in participants consuming a higher dose (96 mg) of sucralose, suggesting potential non-linear dose response relationships or compensatory mechanisms at higher intake levels. Collectively, these findings indicate that chronic sucralose consumption, even without deliberate carbohydrate co-ingestion, may induce subtle metabolic adaptations that could influence long-term glucose homeostasis [26].

In summary, the preponderance of evidence suggests that sucralose consumed alone, particularly in acute or moderate doses, exerts minimal or negligible effects on glucose metabolism, insulin secretion, and glycemic response in most healthy individuals. Long term metabolic neutrality has been demonstrated in several well-controlled trials lasting up to 12 weeks, with no significant alterations in fasting glucose, insulin or HbA1c levels. However, emerging data indicate that sucralose may. Not be entirely metabolically inert as certain populations, particularly non habitual users of non-nutritive sweeteners may experience reductions in insulin sensitivity following short-term or chronic consumption. These context dependent effects underscore the importance of considering individual variability, habitual dietary patterns, and dose-response relationships when evaluating the metabolic safety of sucralose in clinical and public health contexts.

Metabolic Effects of Sucralose Combined with Carbohydrates

Altered Glycemic Control and Amplified Insulin Responses

While sucralose consumed in isolation appears to have minimal metabolic impact in most individuals, a contrasting picture emerges when it is ingested alongside carbohydrates. Accumulating evidence demonstrated that the co-consumption of sucralose with carbohydrate containing foods or beverages can profoundly alter glucose homeostasis, amplify insulin secretion, and reduce insulin sensitivity, effects that are not observed when either substance is consumed independently.

One of the earliest and most influential studies documenting this phenomenon was conducted by Pepino and colleagues in 2013. In this randomized crossover trial, obese individuals who did not regularly consume non-nutritive sweeteners ingested either sucralose or water 10 minutes before an oral glucose tolerance test (OGTT). The results were striking: participants who consumed sucralose prior to the glucose load exhibited significantly higher peak plasma glucose concentrations, increased insulin and C-peptide levels, and a 23% reduction in insulin sensitivity compared to the water control condition. Importantly, the total insulin secretion rate (area under the curve) was greater after sucralose ingestion, and insulin clearance from plasma was reduced by approximately 7%. These findings suggested that sucralose potentiates the glycemic and insulinemic responses to an oral glucose challenge, particularly in individuals with obesity who are not habitual users of artificial sweeteners [27,28].

The mechanisms underlying these effects appear to involve alterations in glucose absorption and insulin secretion dynamics. The authors noted that sucralose increase the early peak in plasma glucose without affecting indices of b-cell sensitivity, suggesting that enhanced glucose absorption rather than altered pancreatic function was the primary driver of the observed metabolic changes. This interpretation is consistent with preclinical evidence demonstrating that sucralose activates sweet taste receptors (T1R2/T1R3) expressed on intestinal enteroendocrine cells and enterocytes, leading to upregulation of sodium glucose cotransporter 1 (SGLT1) and facilitative glucose transporter 2 (GLUT2). In rodent models, sucralose has been shown to double the rate of glucose absorption within minutes by increasing apical GLUT2 expression threefold, an effect mediated by the same phospholipase C-b2 (PLC-b2) signalling pathway activated by high glucose concentrations. Chronic dietary supplementation with sucralose also increases SGLT1 mRNA and protein expression in the intestines of wild type mice, but not lacking T1R3 or a-gustducin, confirming the critical role of sweet taste receptor signalling in this process [22,28,29,30,31].

A landmark study by Dalenberg and colleagues provided compelling evidence that the metabolic effects of sucralose are critically dependent on carbohydrate co-ingestion, in this randomized controlled trial, 45 healthy adults who were not regular consumers of low-calorie sweeteners were assigned to one of three groups: sucralose alone, sucrose (table sugar), or sucralose combined with maltodextrin (a non-sweet carboydrate0. Participants consumed seven 355mL beverages over a two-week period, and metabolic assessments, including oral glucose tolerance tests, functional MRI brain scans, and sensory testing were conducted before and after the intervention. Contrary to the “sweet uncoupling hypothesis,” which posits that consuming sweetness without calories leads to metabolic dysfunction, the researchers found that only the group consuming sucralose with maltodextrin exhibited significant metabolic impairment. Specifically, this group showed a 37-40% increase in first phase insulin response during the OGTT and a reduction in insulin sensitivity while those consuming sucralose alone or sucrose alone experience no adverse changes. Importantly, consuming maltodextrin alone also had no effect, confirming that the combination of sucralose and carbohydrate rather than either component in isolation was responsible for the observed metabolic dysregulation [22].

Long-term consumption of sucralose with carbohydrates appears to exacerbate diet induced metabolic dysfunction. A preclinical study by Tsai and colleagues demonstrated that mice fed a high-fat diet supplemented with sucralose for two weeks exhibited significantly worse glucose intolerance and insulin resistance compared to mice fed a high-fat diet alone. Oral glucose tolerance tests revealed elevated blood glucose levels at 30 minutes, and insulin tolerance tests confirmed reduced insulin sensitivity, as Mechanistic investigations revealed that sucralose activated extracellular signal-regulated kinase1 /2 (ERK1 /2) in a T1R3-dependent manner, leading to impaired insulin signalling in liver cells; importantly, pharmacological inhibition of ERK1 /2 reversed sucralose induced glucose intolerance and insulin resistance,. These findings suggest that chronic sucralose consumption in the context of a high0carbohydrate or high-fat diet can amplify metabolic dysregulation through both peripheral (intestinal glucose transport) and hepatic (insulin signalling) mechanisms [29].

Human studies corroborate these preclinical findings. A controlled trial in young adults found that daily sucralose consumption (at 15% of the acceptable daily intake) for 14 days resulted in a 17.7% decrease in insulin sensitivity, even in the absence of deliberate carbohydrate co-ingestion. However, given that participants were consuming sucralose at mealtimes, inadvertent co-ingestion with dietary carbohydrates likely occurred, potentially explaining the observed effects. Similarly, healthy young adults consuming 48 mg of sucralose daily for 10 weeks exhibited elevated fasting insulin levels and reduced insulin sensitivity during OGTTs, suggesting that habitual sucralose consumption in the context of a typical mixed diet, which invariably includes carbohydrates that can lead to progressive metabolic adaptation [12,20].

The clinical implications of these findings are profound. For individuals seeking to reduce sugar intake and improve metabolic health, consuming sucralose-sweetened beverages alongside meals, particularly carbohydrate rich foods may inadvertently counteract the intended benefits by promoting exaggerated insulin responses, accelerated glucose absorption, and progressive insulin resistance. This context dependent metabolic impact underscores the importance of considering not just the caloric content of foods, but also the nutrient combinations and their interactions with chemomsensory pathways in the gut [19,22,27,29,32].

The Concept of “ Sweet Uncoupling” and Metabolic Mismatch

The paradoxical metabolic effects of sucralose when consumed with carbohydrates have given rise to the concept of “sweet uncoupling” or “metabolic mismatch”, a hypothesis proposing that decoupling sweet taste from caloric content disrupts the body’s learned metabolic responses and impairs glucose homeostasis. However, recent evidence challenges the classical formulation of this hypothesis and suggests a more nuanced mechanism involving inappropriate amplification of glucose absorption rather than simple sensory-metabolic dissociation.

The sweet uncoupling hypothesis, first articulated by Swithers and colleagues, posits that sweet taste serves as a conditioned stimulus that prepares the body for incoming calories by triggering anticipatory physiological responses, such as insulin secretion, incretin release, and metabolic priming. Under normal circumstances, the detection of sweetness in the oral cavity and gastrointestinal tract signals the imminent arrival of glucose, prompting the release of hormones like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) that facilitate glucose uptake and utilization. When sweetness is repeatedly experienced without the expected caloric payload as occurs with non-nutritive sweetener consumption, this conditioned response is hypothesized to weaken over time, leading to reduced incretin secretion, impaired glucose tolerance, and ultimately, increased risk of obesity and type 2 diabetes [22,30,32,33].

Support for the uncoupling hypothesis initially came from rodent studies demonstrating that rats consuming yogurts sweetened inconsistently with sucrose and saccharin gained more weight and exhibited greater glucose intolerance than rats consuming yogurts consistently sweetened with sucrose alone. These findings suggested that the mismatch between sweet taste and caloric content disrupted predictive metabolic signalling, leading to maladaptive responses to subsequent sugar intake. In humans, neuroimaging studies have shown that artificial sweeteners activate brain reward regions less intensely than caloric sugars, potentially reflecting reduced anticipatory metabolic responses and altered dopamine signalling related to energy homeostasis [22,32,33,34].

However, the landmark study by Dalenberg and colleagues fundamentally challenges the sweet uncoupling hypothesis as originally conceived. As described previously, this trial found that consuming sucralose alone (sweet taste without calories) over a two-week period did not impair insulin sensitivity, glucose metabolism, or brain responses to sweet taste in healthy adults. If uncoupling were the primary mechanism, these participants should have exhibited the most pronounced metabolic dysfunction, but they did not. Instead, metabolic impairment occurred specifically when sucralose was consumed in combination with maltodextrin. a scenario in which sweet taste and calories were present simultaneously, albeit from different sources. This finding directly contradicts the uncoupling hypothesis and points toward an alternative mechanism: metabolic mismatch driven by inappropriate sensory amplification of nutrient absorption [22].

The revised conceptual framework emerging from these findings suggests that the gut’s chemosensory apparatus specifically, sweet taste receptors on enteroendocrine cells and enterocytes interprets the simultaneous presence of sucralose and carbohydrate as a signal of exceptionally high glucose availability. Sucralose activates T1R2/T1R3 receptors, triggering upregulation of SGLT1 and insertion of GLUT2 into the apical membrane, thereby priming the intestine for enhanced glucose absorption. When glucose (derived from maltodextrin or dietary carbohydrates) arrives concurrently, this primed absorptive machinery facilitates excessive glucose uptake beyond what would occur in response to the carbohydrate alone. The result is an exaggerated postprandial glycemic excursion, compensatory hyperinsulinemia, and with repeated exposure progressive insulin resistance [22,29,30,34].

Small and colleagues have proposed that this phenomenon may involve the gut generating “inaccurate messages” to the brain about the quantity of calories present. The sweet taste receptor system, activated by both sucralose and glucose-derived from carbohydrates, may signal that double the amount of calories are available than are actually present. Over time, these erroneous signals could produce maladaptive central responses, including reduced sensitivity of brain reward circuits to sweet taste and impaired predictive regulation of glucose metabolism. Indeed, participants in the sucralose-plus-maltodextrin group exhibited blunted brain responses to sucrose in functional MRI scans, despite unchanged sensory perception of sweetness, suggesting central desensitization to sweet taste as a metabolic cue [22].

This metabolic mismatch hypothesis also helps reconcile conflicting findings in the literature regarding artificial sweeteners and glucose homeostasis. Studies that have failed to detect adverse metabolic effects of sucralose have typically administered the sweetener in isolation, without concurrent carbohydrate intake, or have enrolled habitual consumers of non-nutritive sweeteners who may have already adapted to chronic exposure. Conversely, studies demonstrating metabolic impairment have generally involved co-ingestion of sucralose with carbohydrate-containing meals or beverages, or have focused on individuals with obesity or those unaccustomed to artificial sweetener use populations potentially more susceptible to dysregulated glucose absorption. This context-dependence underscores the critical importance of nutrient pairing in determining the metabolic consequences of sucralose consumption [22,24,25,27,35].

From a practical standpoint, the metabolic mismatch paradigm has significant implications for dietary counselling and public health messaging. The widespread consumption of diet sodas, protein shakes, and low-calorie desserts sweetened with sucralose often consumed alongside meals or snacks containing carbohydrates may inadvertently promote metabolic dysregulation by triggering excessive glucose absorption and insulin secretion. Educating consumers and clinicians about the hidden metabolic risks of combining non-nutritive sweeteners with carbohydrate-rich foods is essential for optimizing strategies aimed at preventing obesity, type 2 diabetes, and metabolic syndrome [22].

Mechanistic Insights: Sweet Taste Receptors and Glucose Transporters

Cellular and Molecular Pathways: SLGT1/GLUT2 Upregulation and Incretin Hormone Release

The metabolic effects of sucralose, particularly when consumed with carbohydrates, are mediated by a sophisticated network of sweet taste receptors and nutrient-sensing machinery expressed throughout the gastrointestinal tract. At the molecular level, these interactions trigger cascades that regulate glucose absorption capacity, incretin hormone secretion, and ultimately systemic glucose homeostasis.

The sweet taste receptor complex, comprised of T1R2 and T1R3 subunits that heterodimerize to form the functional T1R2+T1R3 receptor, is expressed not only on the apical membranes of taste receptor cells in the oral cavity but also on specialized enteroendocrine cells lining the small intestinal epithelium. Landmark studies by Margolskee and colleagues established that these gut-expressed sweet taste receptors function as luminal sugar sensors capable of detecting both nutritive sugars and non-nutritive sweeteners like sucralose. When sucralose or dietary sugars bind to T1R2+T1R3 receptors on enteroendocrine cells, they activate a G-protein-coupled signalling cascade involving α-gustducin (the taste-specific Gα subunit), Gβ3, and Gγ13 heterotrimeric G-protein complexes [36,37,38,39].

Figure 1. Signal Transduction Molecules Involves in 5 Taste Qualities [38]

Upon receptor activation, the dissociated βγ subunits of the G-protein stimulate phospholipase C-β2 (PLC-β2), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). IP₃ then binds to IP₃ receptor type 3 (IP₃R3) on the endoplasmic reticulum, triggering the release of intracellular Ca²⁺ stores. This rapid elevation in cytosolic Ca²⁺ activates the transient receptor potential melastatin 5 (TRPM5) cation channel—a calcium-activated, non-selective cation channel that is co-expressed with T1Rs and serves as a common downstream effector for sweet, bitter, and umami taste signalling. TRPM5 activation induces Na⁺ influx, causing membrane depolarization that opens voltage-dependent Ca²⁺ channels (VDCCs), further amplifying intracellular Ca²⁺ levels and ultimately triggering vesicular exocytosis of gut hormones [37,38,40,41].

Figure 2. Sweet Taste Transduction Uses Multiple Pathways in Type II [41]

Critically, this sweet taste receptor signalling pathway in enteroendocrine cells mediates the secretion of incretin hormones, particularly glucagon-like peptide-1 (GLP-1) from L-cells and glucose-dependent insulinotropic polypeptide (GIP) from K-cells. In cultured enteroendocrine GLUTag cells (a model of L-cells), artificial sweeteners including sucralose have been shown to stimulate GLP-1 and GIP secretion in a dose-dependent manner when sweet taste receptors are functionally expressed. However, in human studies, the effects of sucralose alone on incretin secretion have been inconsistent. When sucralose was infused directly into the duodenum of healthy volunteers at concentrations matching the sweetness of sucrose (0.4 mM) or at higher concentrations (4 mM), no significant increases in GLP-1 or GIP were observed compared to saline controls. This discrepancy between in vitro and in vivo findings may reflect species differences in sweet taste receptor expression and functionality, differences in receptor density between enteroendocrine cell lines and native tissue, or the requirement for concurrent nutrient stimulation to amplify receptor signalling [30,36,42,43,44].

The most profound metabolic consequence of sweet taste receptor activation in the gut is the upregulation of intestinal glucose transporters, particularly sodium-glucose cotransporter 1 (SGLT1) and, under certain conditions, glucose transporter 2 (GLUT2). SGLT1, expressed on the apical (luminal-facing) membrane of absorptive enterocytes, is the primary transporter responsible for active glucose absorption from the intestinal lumen. Under basal conditions, SGLT1 expression is constitutively maintained at levels sufficient to absorb physiological amounts of dietary glucose. However, when luminal glucose or sweeteners activate T1R3 and α-gustducin on adjacent enteroendocrine cells, paracrine signalling occurs whereby secreted gut hormones particularly GLP-2, GIP, and possibly GLP-1 bind to receptors on enterocytes and stimulate SGLT1 gene transcription and protein translation [36,45,46,47].

Experimental evidence for this mechanism comes from studies in T1R3 knockout and α-gustducin knockout mice. When wild-type mice were fed a high-carbohydrate diet (70% sucrose) for two weeks, intestinal SGLT1 mRNA expression increased 1.6-fold, SGLT1 protein abundance in brush-border membrane vesicles (BBMV) increased 1.9-fold, and the initial rate of Na⁺-dependent glucose transport into isolated BBMV increased 1.9-fold compared to mice fed a low-carbohydrate diet (1.9% sucrose). However, T1R3 knockout and α-gustducin knockout mice exhibited no such adaptive upregulation of SGLT1 in response to increased dietary carbohydrate, despite consuming identical diets. Importantly, dietary supplementation with artificial sweeteners, including sucralose, also increased SGLT1 mRNA and protein expression in wild-type mice but not in knockout mice lacking T1R3 or α-gustducin. These findings establish that sweet taste receptor signalling is both necessary and sufficient for the adaptive upregulation of intestinal glucose absorption capacity in response to luminal sweeteners [36,45].

Rapid, acute upregulation of SGLT1 can occur within minutes of sweet taste receptor activation. Studies using everted intestinal sleeves demonstrated that exposure to high luminal glucose or artificial sweeteners triggers rapid insertion of SGLT1 into the apical membrane, doubling the rate of glucose absorption within 5–10 minutes. This phenomenon appears to involve both recruitment of pre-formed SGLT1 protein from intracellular vesicular stores and enhanced transcription via sweet taste receptor-mediated signalling. The rapidity of this response suggests that sweet taste receptor activation can prime the intestine for enhanced glucose uptake even before substantial amounts of glucose arrive in the lumen, a mechanism that may confer evolutionary advantages for nutrient acquisition but can become maladaptive in the context of frequent artificial sweetener exposure [45,46].

The role of GLUT2 in apical glucose absorption remains controversial. Under normal dietary conditions, GLUT2 is predominantly localized to the basolateral (blood-facing) membrane of enterocytes, where it facilitates the passive exit of absorbed glucose into the bloodstream. However, some studies have suggested that GLUT2 can be recruited to the apical membrane in response to high luminal glucose concentrations, where it would mediate bulk facilitated diffusion of glucose independent of SGLT1. This “apical GLUT2 hypothesis” has been supported by functional studies showing phlorizin-insensitive (i.e., SGLT1-independent) glucose absorption following high-glucose boluses. However, rigorous investigations using GLUT2 knockout mice and Western blot analysis of isolated brush-border membranes have largely failed to confirm significant apical GLUT2 recruitment. Instead, GLUT2 detected in apical membrane fractions appears to result primarily from contamination with basolateral membranes during isolation procedures. Current consensus holds that SGLT1 remains the dominant pathway for intestinal glucose absorption even under high luminal glucose loads, with GLUT2 serving primarily a basolateral exit function [46,47,48,49,50,51]

Nevertheless, GLUT2 regulation may still be influenced by dietary sweeteners and nutritional programming. Studies in pigs subjected to early weaning demonstrated long-term upregulation of GLUT2 in brush-border membranes accompanied by reciprocal downregulation of SGLT1, suggesting developmental plasticity in the relative contributions of these transporters to glucose handling. Whether chronic sucralose consumption induces similar adaptive shifts in transporter expression in humans remains an important unanswered question [4,21,49].

Incretin hormone secretion from enteroendocrine cells is also critically dependent on SGLT1 function. In human ileal L-cells, glucose-stimulated GLP-1 secretion requires SGLT1-mediated glucose uptake into the cell, followed by intracellular glucose metabolism, closure of ATP-sensitive K⁺ channels (K_ATP), membrane depolarization, and Ca²⁺-dependent vesicular exocytosis. SGLT1 knockout mice exhibit abolished GLP-1 and GIP secretion in response to oral glucose, confirming the essential role of this transporter in glucose-induced incretin release. Interestingly, SGLT1 also plays a direct role in glucose sensing within pancreatic islets, where its loss results in abnormal islet morphology and impaired insulin secretion, suggesting that SGLT1-mediated nutrient sensing is a conserved mechanism across multiple glucose-responsive tissues [42,43,46,52].

The integration of sweet taste receptor signalling with SGLT1-mediated glucose absorption creates a feed-forward loop that amplifies glucose uptake when sweeteners and carbohydrates are consumed together. Sucralose activates sweet taste receptors, triggering incretin secretion and SGLT1 upregulation; simultaneously, dietary carbohydrates provide glucose substrates that are transported via the upregulated SGLT1, further stimulating incretin release through SGLT1-dependent glucose sensing. This dual mechanism explains why sucralose consumed with carbohydrates produces exaggerated glycemic and insulinemic responses compared to either substance alone [42,43,46,47,48,49,50,51].

Intestinal Adaptation: Sensing “Sweet with Calorie” versus “Sweet without Calorie”

The intestinal chemosensory system possesses remarkable plasticity, adapting its nutrient-sensing machinery in response to chronic dietary patterns. Central to understanding the differential metabolic effects of sucralose is elucidating how the gut distinguishes between “sweet with calorie” (nutritive sugars) and “sweet without calorie” (non-nutritive sweeteners), and how repeated exposure to these distinct stimuli shapes long-term intestinal function.

Under physiological conditions, the simultaneous presence of sweet taste (signalled via T1R2+T1R3 receptors) and calories (detected via glucose metabolism and SGLT1-mediated uptake) provides concordant signals that appropriately calibrate glucose absorption capacity and incretin secretion to match nutritional intake. When natural sugars like sucrose or glucose are consumed, sweet taste receptors are activated on enteroendocrine cells, while glucose is simultaneously transported into enterocytes via SGLT1, undergoing intracellular metabolism that generates ATP. The rise in intracellular ATP closes K_ATP channels, causing membrane depolarization, Ca²⁺ influx, and secretion of GLP-1 and GIP. Concurrently, sweet taste receptor activation on enteroendocrine cells triggers PLC-β2/IP₃/TRPM5-mediated Ca²⁺ signalling that also promotes incretin release. These two pathways, one metabolic (SGLT1-dependent) and one receptor-mediated (T1R2+T1R3-dependent) operate in parallel and converge to produce robust, coordinated incretin secretion and appropriate insulin responses [22,33,53,54].

Oral glucose sensing studies in humans have confirmed that glucose engages both pathways. When healthy volunteers performed rinse-and-expectorate tests with glucose in the presence of the T1R receptor inhibitor Na-lactisole, glucose detection thresholds increased only threefold, whereas sucralose detection thresholds increased more than eightfold, indicating that glucose utilizes an additional signalling pathway beyond sweet taste receptors. Similarly, addition of sodium (NaCl) lowered glucose detection thresholds by approximately 50% (by enhancing SGLT-mediated transport), whereas it raised sucralose detection thresholds (by cognitively masking the sweet taste). Application of the SGLT inhibitor phlorizin impaired detection of glucose and the non-metabolizable glucose analog α-methyl-D-glucopyranoside (MDG) more than it did sucralose or fructose, confirming that glucose sensing involves both T1R2+T1R3 sweet taste receptors and SGLT transporters. This dual-pathway model provides the gut with redundant mechanisms to ensure accurate nutrient detection and appropriate metabolic responses [55].

In contrast, when sucralose is consumed alone “sweet without calorie”, only the sweet taste receptor pathway is activated, while the metabolic glucose-sensing pathway remains quiescent. Importantly, as demonstrated by Dalenberg and colleagues, activation of sweet taste receptors in the absence of concurrent caloric intake does not appear to impair subsequent metabolic or neural responses to sugar. Participants who consumed sucralose-sweetened beverages without carbohydrates for 10 days exhibited no changes in insulin sensitivity, glucose metabolism, or brain responses to sweetness. This finding challenges the classical “sweet uncoupling hypothesis,” which predicted that repeated exposure to sweetness without calories would weaken conditioned metabolic responses and lead to glucose intolerance. Instead, the data suggest that the gut and brain can tolerate occasional mismatches between sweet taste and caloric content without significant metabolic dysfunction at least over short timeframes in healthy individuals [22,33].

However, the situation changes dramatically when sucralose is consumed with carbohydrates creating a scenario of “sweet with calorie” but from discordant sources. In this context, sucralose activates sweet taste receptors and upregulates SGLT1 expression, while simultaneously arriving dietary glucose is absorbed via the primed SGLT1 transporters, generating an amplified glucose signal. The intestine interprets this combination as indicating an exceptionally high luminal glucose load far greater than what would be expected from either sucralose or carbohydrate alone. Functional MRI studies have shown that participants consuming sucralose plus maltodextrin exhibited reduced brain responses to sucrose compared to baseline, despite unchanged sensory perception of sweetness. This central desensitization may reflect the brain receiving “inaccurate messages” about caloric availability, leading to maladaptive recalibration of reward and metabolic regulatory circuits [22,34].

At the intestinal level, chronic exposure to artificial sweeteners may induce adaptive changes in sweet taste receptor expression and glucose transporter abundance. Studies in mice maintained on sucralose-supplemented diets for 8–12 weeks have reported upregulation of T1R2 and T1R3 receptor mRNA and protein in both tongue and small intestinal epithelium. This upregulation may reflect compensatory responses to chronic sweet receptor activation, potentially increasing sensitivity to sweetness and further dysregulating SGLT1 expression. Conversely, some studies have reported blunting of sweet taste perception following prolonged artificial sweetener consumption, suggesting receptor desensitization or downregulation of downstream signalling components. The directionality and magnitude of these adaptive changes likely depend on dose, duration of exposure, concurrent dietary patterns, and individual variability in taste receptor genetics [4,21,56].

The gut microbiome also mediates intestinal adaptation to chronic sucralose exposure. Prolonged sucralose consumption has been associated with reductions in beneficial bacterial phyla (e.g.,Firmicutes and Bacteroidetes), decreases in butyrate-producing species, and increases in pro-inflammatory taxa such as Ruminococcaceae. These microbial shifts can alter production of short-chain fatty acids (SCFAs), which serve as signalling molecules that bind to G-protein-coupled receptors (GPCRs) on enteroendocrine cells and modulate incretin secretion and glucose homeostasis. Dysbiosis induced by sucralose may therefore indirectly impair glucose sensing and metabolic regulation by disrupting the normal microbiota-gut-brain signalling axis [21,57].

Furthermore, chronic sucralose consumption may alter the balance between SGLT1 and GLUT2 expression in the intestinal epithelium. While acute sucralose exposure upregulates SGLT1 in a T1R3-dependent manner, prolonged exposure, particularly in the context of high-carbohydrate diets may trigger compensatory downregulation of SGLT1 or reciprocal upregulation of GLUT2 to prevent excessive glucose absorption. Developmental programming studies have shown that nutritional interventions during critical periods can induce long-lasting shifts in the relative contributions of SGLT1 versus GLUT2 to glucose transport, with implications for metabolic health across the lifespan. Whether habitual sucralose consumption induces similar developmental or adaptive programming of intestinal glucose transporters in humans represents an important area for future investigation [4,16,21,45,49].

In summary, the intestinal chemosensory system integrates sweet taste receptor signalling with metabolic glucose sensing to calibrate absorption capacity and incretin secretion. Nutritive sugars activate both pathways concordantly, producing appropriate metabolic responses. Sucralose consumed alone activates only sweet taste receptors without triggering metabolic dysfunction in most individuals over the short term. However, sucralose consumed with carbohydrates creates discordant signals that dysregulate glucose absorption, amplify insulin secretion, and may lead to central desensitization of reward circuits. Chronic exposure to sucralose can induce adaptive changes in receptor expression, transporter abundance, and gut microbiota composition, with potential long-term consequences for glucose homeostasis and metabolic health.

Neuroendocrine and Reward Pathway Responses

The metabolic consequences of sucralose consumption, particularly when combined with carbohydrates, extend beyond peripheral glucose handling to involve profound alterations in central nervous system processing of sweet taste, reward signalling, and appetite regulation. Emerging evidence from functional neuroimaging studies reveals that the combination of sucralose and carbohydrates disrupts brain regions critical for encoding the rewarding and metabolic properties of food, with potential long-term implications for eating behaviour, satiety, and energy balance.

Central to understanding the neuroendocrine effects of sucralose is the concept of dual nutrient sensing: the brain evaluates food not only through sensory properties like sweetness but also through post-ingestive metabolic signals such as glucose utilization and incretin hormone release. Under normal physiological conditions, consuming nutritive sugars like sucrose or glucose simultaneously activates sweet taste receptors on the tongue and triggers robust increases in blood glucose, insulin, and satiety hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). These peripheral metabolic signals are detected by the brain, which integrates them with sweet taste information to generate appropriate reward responses and regulate subsequent food intake [58,59,60].

Functional magnetic resonance imaging (fMRI) studies have consistently demonstrated that sucrose activates brain regions involved in reward processing including the striatum (caudate and putamen), midbrain dopaminergic nuclei, anterior insula/frontal operculum (AI/FO), and anterior cingulate cortex (ACC)—more robustly than non-nutritive sweeteners like sucralose. Frank and colleagues reported that when healthy women tasted sucrose versus sucralose, sucrose elicited significantly greater activation in the AI/FO, ventral striatum, dorsal caudate, and ACC. These brain regions are part of the mesolimbic dopamine reward circuitry, which encodes the hedonic value and motivational salience of food. The differential activation patterns suggest that the brain can distinguish between caloric and non-caloric sweet tastants, with nutritive sugars producing more robust reward signals [58,59,60].

The neurobiological basis for this differential response involves striatal dopamine signalling, which plays a critical role in encoding the caloric content of sweet solutions independent of sweetness perception. Tellez and colleagues demonstrated in mice that oral glucose intake produces significantly greater dopamine efflux in the dorsal striatum compared to the artificial sweetener sucralose. This enhanced dopamine release is driven by glucose utilization: when glucose oxidation was pharmacologically blocked using 2-deoxyglucose (2-DG), dopamine efflux during glucose intake was suppressed to levels similar to those observed during sucralose consumption. Conversely, enhancing glucose oxidation with dichloroacetate during sucralose intake restored dopamine efflux to levels comparable to glucose, confirming that glucose metabolism not sweet taste per se, drives striatal dopamine release. These findings establish that the brain’s reward system is exquisitely sensitive to the metabolic properties of ingested nutrients, using dopamine signalling to encode caloric value and guide goal-directed feeding behaviour [60,61].

The landmark study by Dalenberg and colleagues provides compelling evidence that consuming sucralose in combination with carbohydrates impairs central sensitivity to sweet taste and disrupts predictive metabolic responses. As previously described, healthy adults who consumed seven beverages containing sucralose plus maltodextrin over two weeks exhibited reduced insulin sensitivity and blunted brain responses to sweet taste during subsequent fMRI assessments. Specifically, the sucralose-plus-carbohydrate group showed significantly reduced BOLD (blood-oxygen-level-dependent) signal responses to sucrose in the midbrain, insular cortex, and cingulate cortex compared to baseline, brain regions critical for sweet taste processing and reward signalling. Importantly, this neural desensitization occurred despite unchanged sensory perception of sweetness, indicating that the impairment was central (metabolic and reward-related) rather than perceptual [22].

Critically, the magnitude of reduction in midbrain and striatal responses to sweet taste correlated with the degree of insulin resistance induced by the intervention. Participants who exhibited the greatest decreases in insulin sensitivity also showed the most pronounced reductions in sweet-evoked brain activation in dopaminergic reward regions. This correlation suggests a mechanistic link between peripheral metabolic dysfunction and central reward processing: consuming sucralose with carbohydrates not only impairs glucose metabolism but also diminishes the brain’s ability to appropriately encode the rewarding properties of sugar, potentially creating a vicious cycle of dysregulated eating behaviour and metabolic decline [22].

The proposed mechanism underlying this central desensitization involves inappropriate amplification of sweet taste and nutrient signals during sucralose-carbohydrate co-ingestion. As articulated by Small and colleagues, the gut’s chemosensory apparatus activated by both sucralose (via sweet taste receptors) and dietary carbohydrates (via glucose metabolism) may signal to the brain that double the amount of calories are present than actually exist. Over repeated exposures, these “inaccurate messages” about caloric availability could lead to maladaptive recalibration of central reward circuits, resulting in reduced dopaminergic responses to sweet taste and impaired predictive regulation of glucose metabolism. Neuroimaging evidence supports this interpretation: participants consuming sucralose with maltodextrin exhibited blunted brain responses specifically to sweet (but not sour, salty, or savory) tastes, suggesting selective desensitization of sweet reward pathways [22].

Beyond reward processing, sucralose consumption particularly in the presence of carbohydrates profoundly affects hypothalamic regulation of appetite and satiety. The hypothalamus serves as the brain’s master regulator of energy homeostasis, integrating peripheral signals about nutrient availability (glucose, insulin, leptin, GLP-1) with central neural inputs to control hunger, satiety, and energy expenditure. Recent fMRI studies by Page and colleagues reveal that sucralose increases hypothalamic blood flow and neural activity compared to both sugar and water, with particularly pronounced effects in individuals with obesity [22].

In a randomized crossover trial involving 75 participants stratified by sex and body weight status, acute consumption of sucralose-sweetened beverages increased hypothalamic activation and heightened subjective feelings of hunger compared to glucose-sweetened beverages. Notably, while glucose consumption raised blood sugar levels and triggered release of satiety hormones (GLP-1, GIP, insulin), thereby reducing hunger and hypothalamic activity, sucralose failed to stimulate these hormonal responses despite delivering an equally sweet taste. This hormonal disconnect sweetness without caloric feedback appears to confuse the hypothalamus, leading to sustained hunger signals even in the absence of true energy deficit [62].

Functional connectivity analyses revealed that sucralose consumption altered communication between the hypothalamus and other brain regions involved in motivation, decision-making, and sensory processing, including the anterior cingulate cortex (ACC) and prefrontal cortex. These changes in neural connectivity were most pronounced in individuals with obesity and in female participants, suggesting that individual characteristics such as sex, adiposity, and insulin resistance modulate the hypothalamic response to non-caloric sweeteners. The investigators proposed that this “mismatch” between sweet taste expectation and actual energy delivery may lead to different hypothalamic activation patterns with sucralose versus caloric sweeteners, potentially influencing appetite regulation and metabolic responses over time [62,63].

Additional mechanistic insights come from studies examining the interaction between sucralose and leptin signalling. Leptin, secreted by adipocytes in proportion to body fat mass, acts on hypothalamic neurons to suppress appetite and increase energy expenditure. Chronic hyperleptinemia, however, leads to leptin resistance, raising the threshold for satiety and promoting overeating. Kohno and colleagues discovered that hypothalamic neurons activated by leptin are also stimulated by sucralose, suggesting that sucralose consumption could potentially disrupt the appetite-satiety axis and contribute to dysregulation of energy homeostasis. Furthermore, Velázquez and colleagues reported that sucralose consumption in rats increased expression of ΔFosB, a transcription factor associated with chronic neural activation—in dopaminergic brain nuclei, promoting food intake and suggesting a potential link between sucralose consumption and dysregulation of neural mechanisms controlling feeding behaviour [21,64].

The implications of these neuroendocrine effects for eating behaviour, satiety, and energy balance are profound yet complex. On one hand, acute studies have demonstrated that sucralose consumption can reduce neural activity in brain regions associated with food cue reactivity and food valuation, potentially decreasing appetite and energy intake in the short term. Zhang and colleagues found that acute sucralose ingestion (relative to water) reduced monetary bids on food items during a Food Bid Task and decreased activity in brain regions linked to food reward, including the visual cortex, dorsolateral prefrontal cortex, and posterior cingulate. These findings suggest that sucralose may exert transient appetite-suppressive effects, consistent with some short-term randomized controlled trials reporting reduced energy intake following artificial sweetener consumption [65,66,67].

However, the long-term consequences appear far more concerning, particularly when sucralose is consumed habitually with carbohydrate-containing meals. Chronic exposure to the sweet-calorie mismatch may progressively desensitize reward circuits, diminish satiety hormone responses, and increase hypothalamic hunger signalling. These neuroadaptations could drive compensatory increases in food intake, preference shifts toward highly palatable foods, and difficulty achieving satiety factors that collectively promote positive energy balance and weight gain despite the absence of calories from sucralose itself. Indeed, rodent studies have demonstrated that chronic consumption of saccharin-sweetened foods leads to greater weight gain and adiposity compared to glucose-sweetened foods, an effect attributed to disrupted learned associations between sweet taste and caloric consequences [68,69].

Meta-analyses of randomized controlled trials examining the effects of artificial sweeteners on energy intake and body weight have yielded mixed results, reflecting the complexity of these neuroendocrine interactions and the importance of study design, population characteristics, and dietary context. Short-term trials (≤1 day to 12 weeks) generally report reduced energy and sugar intake when artificial sweeteners replace caloric sweeteners, with modest or neutral effects on body weight. However, longer-term observational studies have raised concerns about potential associations between habitual artificial sweetener consumption and increased risk of weight gain, obesity, and metabolic syndrome. These paradoxical findings may be explained, in part, by the differential effects of sucralose when consumed in isolation versus with carbohydrates, as well as individual variability in neural and metabolic responses based on sex, adiposity, insulin resistance, and prior sweetener exposure [22,68,70].

Importantly, compensatory energy intake following sucralose consumption does not appear to completely offset the caloric reduction achieved by replacing sugar, suggesting that artificial sweeteners may still confer net benefits for weight management in certain contexts. However, the potential for sucralose to dysregulate central reward processing, impair satiety signalling, and increase hypothalamic hunger responses, particularly when consumed with carbohydrates underscores the need for caution and individualized dietary counselling. For individuals with obesity, insulin resistance, or heightened reward sensitivity, the neuroendocrine perturbations induced by sucralose may outweigh any benefits derived from caloric reduction, necessitating careful consideration of alternative strategies for reducing sugar intake [22,67,70].

In summary, sucralose consumption, particularly in combination with carbohydrates, profoundly alters brain reward circuits and hypothalamic regulation of appetite. The co-ingestion of sucralose with carbohydrates reduces striatal and midbrain responses to sweet taste, impairs predictive metabolic signalling, and correlates with decreased insulin sensitivity. Simultaneously, sucralose increases hypothalamic hunger signalling and fails to trigger satiety hormone release, creating a neurometabolic mismatch that may drive increased food intake and disrupt energy balance. These effects are modulated by individual characteristics including sex, adiposity, and insulin resistance, highlighting the need for personalized approaches to artificial sweetener consumption in the context of metabolic disease prevention.

Gut Microbiome and Metabolic Crosstalk

The gut microbiome, a diverse ecosystem of trillions of bacteria, plays a critical role in metabolic homeostasis, immune regulation, and nutrient absorption. Growing evidence reveals that sucralose can induce significant shifts in microbial composition, influencing host metabolism even more profoundly when consumed with carbohydrate

Recent randomized clinical trials and animal studies have demonstrated that long-term sucralose consumption induces gut dysbiosis, a reduction in microbial diversity and alterations in the relative abundance of key taxa. In healthy young adults, ten weeks of daily sucralose intake led to measurable changes in gut microbiota, notably affecting the phylum Firmicutes and diminishing beneficial butyrate-producing species like Blautia coccoides. This shift is concerning, as Blautia coccoides helps maintain normoglycemia and protects against metabolic syndrome. By decreasing butyrate levels, sucralose consumption may increase postprandial glucose excursions and reduce insulin sensitivity, suggesting an inverse relationship between these bacteria and glycemic control. Similar trends have been observed in animal models, where sucralose increased the abundance of Firmicutes (such as Clostridium symbiosum and Peptostreptococcus anaerobius), reduced Bacteroidetes, and promoted the growth of pro-inflammatory species like Staphylococcus and Streptococcus [25,71,72,73].

Beyond compositional shifts, sucralose-induced microbiome changes may mediate inflammatory pathways implicated in insulin resistance and altered metabolic phenotypes. Mouse studies reveal that sucralose consumption elevates pro-inflammatory gene expression in the liver and gut, including genes involved in LPS synthesis, flagellum and fimbriae production, and various bacterial toxin pathways. LPS (lipopolysaccharide), a key bacterial endotoxin, can cross the intestinal barrier to trigger systemic low-grade inflammation, a well-established driver of insulin resistance. Moreover, sucralose has been shown to increase fecal Curli protein, acetate, and branched-chain amino acids, all associated with heightened inflammatory tone in the gut and liver. These pro-inflammatory changes were linked to reduced insulin sensitivity and increased glucose AUC following a mixed meal tolerance test in humans, with the effect magnified by concurrent carbohydrate intake [25,72].

Notably, the adverse impact of sucralose on gut microbial composition and inflammation seems to be context dependent. In studies where sucralose was ingested with a carbohydrate-rich diet, the dysbiotic and inflammatory effects were pronounced, leading to exacerbation of glucose intolerance and insulin resistance. Conversely, some preclinical data suggest sucralose may help preserve intestinal barrier integrity and reduce inflammation in models of colitis when administered without excess dietary carbohydrate, illustrating the complexity and bidirectionality of microbiome-host interactions [29,71,73,74].

Collectively, these findings imply that sucralose consumption especially when paired with carbohydrates can disrupt the delicate balance of gut microbial populations, promote low-grade inflammation, alter key microbial metabolites (such as butyrate and acetate), and contribute to impaired insulin signalling and glucose homeostasis. The interplay between non-nutritive sweeteners, dietary nutrients, and microbial ecology warrants further investigation, given its profound implications for metabolic disease risk and prevention.

Clinical and Public Health Implications

For patient counselling, emphasize that sucralose may be metabolically neutral when consumed alone, such as in black coffee or unsweetened drinks, but risks arise when combined with carbohydrates, potentially worsening glycemic control and insulin sensitivity, particularly in those with obesity or diabetes. Public health messages should caution against viewing artificial sweeteners as universally safe alternatives, especially in mixed meals or snacks. People aiming for metabolic disease prevention should prioritize minimally processed, whole-food diets and be aware that habitual use of sucralose with carbohydrates might increase risk for insulin resistance and gut dysbiosis. Sucralose may benefit some individuals seeking sugar reduction if used strategically, but regular mixed consumption could undermine metabolic goals [4,21,75,76,77].

Future Directions and Research Gaps

Current evidence is limited by short study durations, small sample sizes, and variability in dietary context, particularly the lack of long-term, real-world data on sucralose co-ingestion with carbohydrates. Many studies fail to address individual differences in metabolic response, the interplay with gut microbiota, and specific risks for vulnerable groups. Future research should focus on exploring personalized metabolic effects, longer-term impacts on glucose homeostasis, and detailed microbiome changes. There is a clear need for interventional studies that assess habitual sucralose–carbohydrate pairing and develop evidence-based dietary guidelines to optimize use of non-nutritive sweeteners for metabolic health [4,21,77].

Conclusion

Sucralose, one of the most widely used non-nutritive sweeteners, demonstrates distinct metabolic effects depending on its dietary context. When consumed alone, current evidence supports its relative metabolic neutrality in healthy individuals. However, when sucralose is ingested together with carbohydrates, it can amplify postprandial insulin responses, alter glucose absorption, integrate with sweet taste receptor pathways, modulate neuroendocrine signals, and shift the gut microbiome toward dysbiosis, changes that may contribute to inflammation and insulin resistance, especially in those at risk for metabolic disease.

Clinical and public health recommendations should carefully consider these differential effects. While sucralose may offer benefits for sugar reduction if used strategically, the routine pairing of sucralose with carbohydrate rich foods may undermine metabolic health goals for vulnerable populations. Future research must address long-term impacts, clarify personalized responses, and inform evidence-based guidelines regarding non-nutritive sweetener use alongside carbohydrates, ultimately, context and individual risk should guide sucralose consumption strategies in the prevention and management of metabolic disease.

References

  1. Sucralose [Internet]. Nih.gov. PubChem; 2019. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Sucralose
  2. Sucralose – an overview | ScienceDirect Topics [Internet]. www.sciencedirect.com. Available from: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/sucralose
  3. Schiffman SS, Rother KI. Sucralose, A Synthetic Organochlorine Sweetener: Overview Of Biological Issues. Journal of Toxicology and Environmental Health, Part B [Internet]. 2013 Nov 12;16(7):399–451. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856475/
  4. Ankul Singh S, Singh S, Rukaiah Fatma Begum, Vijayan S, Chitra Vellapandian. Unveiling the profound influence of sucralose on metabolism and its role in shaping obesity trends. Frontiers in Nutrition. 2024 Jul 2;11.
  5. Sugar Replacers – Action on Sugar [Internet]. www.actiononsugar.org. Available from: https://www.actiononsugar.org/sugar-and-health/what-is-sugar/sugar-replacers/
  6. Roberts A, Renwick AG, Sims J, Snodin DJ. Sucralose metabolism and pharmacokinetics in man. Food and Chemical Toxicology. 2000 Jul;38:31–41.
  7. Sucralose is safe, as confirmed by wealth of research and food safety authorities around the world – International Sweeteners Association [Internet]. International Sweeteners Association. 2018 [cited 2025 Nov 3]. Available from: https://www.sweeteners.org/sucralose-is-safe-as-confirmed-by-wealth-of-research-and-food-safety-authorities-around-the-world/
  8. Spencer M, Gupta A, Dam LV, Shannon C, Menees S, Chey WD. Artificial Sweeteners: A Systematic Review and Primer for Gastroenterologists. Journal of Neurogastroenterology and Motility [Internet]. 2016 Apr 30 [cited 2019 Nov 25];22(2):168–80. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819855/
  9. Moriconi E, Feraco A, Marzolla V, Infante M, Lombardo M, Fabbri A, et al. Neuroendocrine and Metabolic Effects of Low-Calorie and Non-Calorie Sweeteners. Frontiers in Endocrinology. 2020 Jul 16;11.
  10. Ruiz-Ojeda FJ, Plaza-Díaz J, Sáez-Lara MJ, Gil A. Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials. Advances in Nutrition. 2019 Jan 1;10(suppl_1):S31–48.
  11. John BA, Wood SG, Hawkins DR. The pharmacokinetics and metabolism of sucralose in the mouse. Food and Chemical Toxicology. 2000 Jul;38:107–10.
  12. Risdon S, Battault S, Romo-Romo A, Roustit M, Briand L, Meyer G, et al. Sucralose and Cardiometabolic Health: Current Understanding from Receptors to Clinical Investigations. Advances in Nutrition [Internet]. 2021 Feb 12;12(4):1500–13. Available from: https://academic.oup.com/advances/article/12/4/1500/6134197?login=true
  13. Jang HJ ., Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim BJ ., Zhou J, et al. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proceedings of the National Academy of Sciences. 2007 Aug 27;104(38):15069–74.
  14. Kojima I, Nakagawa Y. The Role of the Sweet Taste Receptor in Enteroendocrine Cells and Pancreatic β-Cells. Diabetes & Metabolism Journal. 2011;35(5):451.
  15. Sclafani A. Sweet taste signaling in the gut. Proceedings of the National Academy of Sciences [Internet]. 2007 Sep 12;104(38):14887–8. Available from: https://www.pnas.org/content/104/38/14887
  16. Margolskee RF, Dyer J, Kokrashvili Z, Salmon KSH, Ilegems E, Daly K, et al. T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proceedings of the National Academy of Sciences. 2007 Aug 27;104(38):15075–80.
  17. Risdon S, Battault S, Romo-Romo A, Roustit M, Briand L, Meyer G, et al. Sucralose and Cardiometabolic Health: Current Understanding from Receptors to Clinical Investigations. Advances in Nutrition [Internet]. 2021 Feb 12;12(4):1500–13. Available from: https://academic.oup.com/advances/article/12/4/1500/6134197?login=true
  18. Ma J, Chang J, Checklin HL, Young RL, Jones KL, Horowitz M, et al. Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects. British Journal of Nutrition. 2010 Apr 27;104(6):803–6.
  19. Pang MD, Goossens GH, Blaak EE. The Impact of Artificial Sweeteners on Body Weight Control and Glucose Homeostasis. Frontiers in Nutrition [Internet]. 2020;7:598340. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7817779/
  20. Bueno-Hernández N, Esquivel-Velázquez M, Alcántara-Suárez R, Gómez-Arauz AY, Espinosa-Flores AJ, de León-Barrera KL, et al. Chronic sucralose consumption induces elevation of serum insulin in young healthy adults: a randomized, double blind, controlled trial. Nutrition Journal. 2020 Apr 13;19(1).
  21. José Alfredo Aguayo-Guerrero, Lucía Angélica Méndez-García, Solleiro-Villavicencio H, Viurcos-Sanabria R, Escobedo G. Sucralose: From Sweet Success to Metabolic Controversies—Unraveling the Global Health Implications of a Pervasive Non-Caloric Artificial Sweetener. Life [Internet]. 2024 Feb 29;14(3):323–3. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10971371/
  22. Dalenberg JR, Patel BP, Denis R, Veldhuizen MG, Nakamura Y, Vinke PC, et al. Short-Term Consumption of Sucralose with, but Not without, Carbohydrate Impairs Neural and Metabolic Sensitivity to Sugar in Humans. Cell Metabolism [Internet]. 2020 Mar 3;31(3):493-502.e7. Available from: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30057-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413120300577%3Fshowall%3Dtrue
  23. Grotz VL, Pi-Sunyer X, Porte D, Roberts A, Richard Trout J. A 12-week randomized clinical trial investigating the potential for sucralose to affect glucose homeostasis. Regulatory Toxicology and Pharmacology. 2017 Aug;88:22–33.
  24. Mohan V, Manasa VS, Abirami K, Unnikrishnan R, Gayathri R, Geetha G, et al. Effect of Replacing Sucrose in Beverages with Nonnutritive Sweetener Sucralose on Cardiometabolic Risk Factors Among Asian Indian Adults with Type 2 Diabetes: A 12-Week Randomized Controlled Trial. Diabetes Therapy. 2024 Jul 24;15(9):2061–77.
  25. Romo-Romo A, Aguilar-Salinas CA, Brito-Córdova GX, Gómez-Díaz RA, Almeda-Valdes P. Sucralose decreases insulin sensitivity in healthy subjects: a randomized controlled trial. The American Journal of Clinical Nutrition. 2018 Sep 1;108(3):485–91.
  26. Bueno-Hernández N, Esquivel-Velázquez M, Alcántara-Suárez R, Gómez-Arauz AY, Espinosa-Flores AJ, de León-Barrera KL, et al. Chronic sucralose consumption induces elevation of serum insulin in young healthy adults: a randomized, double blind, controlled trial. Nutrition Journal. 2020 Apr 13;19(1).
  27. Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S. Sucralose Affects Glycemic and Hormonal Responses to an Oral Glucose Load. Diabetes Care. 2013;36(9):2530–5.
  28. Pepino MY. Metabolic effects of non-nutritive sweeteners. Physiology & Behavior [Internet]. 2015 Dec;152(152):450–5. Available from: https://www.sciencedirect.com/science/article/pii/S0031938415003728
  29. Tsai MJ, Li CH, Wu HT, Kuo HY, Wang CT, Pai HL, et al. Long-Term Consumption of Sucralose Induces Hepatic Insulin Resistance through an Extracellular Signal-Regulated Kinase 1/2-Dependent Pathway. Nutrients [Internet]. 2023 Jan 1;15(12):2814. Available from: https://www.mdpi.com/2072-6643/15/12/2814
  30. Ma J, Bellon M, Wishart JM, Young R, Blackshaw LA, Jones KL, et al. Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects. American Journal of Physiology Gastrointestinal and Liver Physiology [Internet]. 2009 Apr 1;296(4):G735-739. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19221011
  31. Overduin J, Jansen A. Conditioned Insulin and Blood Sugar Responses in Humans in Relation to Binge Eating. Physiology & Behavior. 1997 Apr;61(4):569–75.
  32. Pepino MY. Metabolic effects of non-nutritive sweeteners. Physiology & Behavior [Internet]. 2015 Dec;152(152):450–5. Available from: https://www.sciencedirect.com/science/article/pii/S0031938415003728
  33. Burke MV, Small DM. Physiological mechanisms by which non-nutritive sweeteners may impact body weight and metabolism. Physiology & Behavior. 2015 Dec;152:381–8.
  34. Veldhuizen MG, Babbs RK, Patel B, Fobbs W, Kroemer NB, Garcia E, et al. Integration of Sweet Taste and Metabolism Determines Carbohydrate Reward. Current biology: CB [Internet]. 2017 Aug 21 [cited 2022 Aug 11];27(16):2476-2485.e6. Available from: https://pubmed.ncbi.nlm.nih.gov/28803868/
  35. Magnuson BA, Roberts A, Nestmann ER. Critical review of the current literature on the safety of sucralose. Food and Chemical Toxicology [Internet]. 2017 Aug;106:324–55. Available from: https://www.sciencedirect.com/science/article/pii/S0278691517302818
  36. Margolskee RF, Dyer J, Kokrashvili Z, Salmon KSH, Ilegems E, Daly K, et al. T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proceedings of the National Academy of Sciences. 2007 Aug 27;104(38):15075–80.
  37. Kyriazis GA, Soundarapandian MM, Tyrberg B. Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proceedings of the National Academy of Sciences of the United States of America [Internet]. 2012 Feb 21 [cited 2021 Oct 5];109(8):E524-532. Available from: https://pubmed.ncbi.nlm.nih.gov/22315413/
  38. Ishimaru Y, Matsunami H. Transient Receptor Potential (TRP) Channels and Taste Sensation. Journal of Dental Research. 2009 Mar;88(3):212–8.
  39. Moran AW, Al-Rammahi MA, Arora DK, Batchelor DJ, Coulter EA, Daly K, et al. Expression of Na+/glucose co-transporter 1 (SGLT1) is enhanced by supplementation of the diet of weaning piglets with artificial sweeteners. British Journal of Nutrition. 2010 Mar 26;104(5):637–46.
  40. Rozengurt E, Sternini C. Taste receptor signaling in the mammalian gut. Current Opinion in Pharmacology. 2007 Dec;7(6):557–62.
  41. Molitor EV, Riedel K, Krohn M, Hafner M, Rudolf R, Cesetti T. Sweet Taste Is Complex: Signaling Cascades and Circuits Involved in Sweet Sensation. Frontiers in Human Neuroscience [Internet]. 2021;15:667709. Available from: https://pubmed.ncbi.nlm.nih.gov/34239428/
  42. Ezcurra M, Reimann F, Gribble FM, Emery E. Molecular mechanisms of incretin hormone secretion. Current Opinion in Pharmacology [Internet]. 2013 Dec 1 [cited 2021 Mar 21];13(6):922–7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838618/
  43. Sun EW, de Fontgalland D, Rabbitt P, Hollington P, Sposato L, Due SL, et al. Mechanisms Controlling Glucose-Induced GLP-1 Secretion in Human Small Intestine. Diabetes. 2017 Apr 6;66(8):2144–9.
  44. Yamane S, Harada N, Inagaki N. Physiology and clinical applications of GIP. Endocrine Journal. 2025;
  45. Stearns AT, Balakrishnan A, Rhoads DB, Tavakkolizadeh A. Rapid Upregulation of Sodium-Glucose Transporter SGLT1 in Response to Intestinal Sweet Taste Stimulation. Annals of Surgery. 2010 May;251(5):865–71.
  46. Röder PV, Geillinger KE, Zietek TS, Thorens B, Koepsell H, Daniel H. The Role of SGLT1 and GLUT2 in Intestinal Glucose Transport and Sensing. Alemany M, editor. PLoS ONE [Internet]. 2014 Feb 26;9(2):e89977. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089977
  47. Duca FA, Waise TMZ, Peppler WT, Lam TKT. The metabolic impact of small intestinal nutrient sensing. Nature Communications [Internet]. 2021 Feb 10;12(1):903. Available from: https://www.nature.com/articles/s41467-021-21235-y
  48. Dyer J, Daly K, Salmon KSH, Arora DK, Kokrashvili Z, Margolskee RF, et al. Intestinal glucose sensing and regulation of intestinal glucose absorption. Biochemical Society Transactions. 2007 Oct 25;35(5):1191–4.
  49. Li Y, Thelen KM, Fernández KM, Nelli R, Fardisi M, Rajput M, et al. Developmental alterations of intestinal SGLT1 and GLUT2 induced by early weaning coincides with persistent low-grade metabolic inflammation in female pigs. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2022 Mar 1;322(3):G346–59.
  50. Ait-Omar A, Monteiro-Sepulveda M, Poitou C, Le Gall M, Cotillard A, Gilet J, et al. GLUT2 Accumulation in Enterocyte Apical and Intracellular Membranes: A Study in Morbidly Obese Human Subjects and ob/ob and High Fat-Fed Mice. Diabetes. 2011 Aug 18;60(10):2598–607.
  51. Naftalin RJ. Does apical membrane GLUT2 have a role in intestinal glucose uptake? F1000Research. 2014 Dec 12;3:304.
  52. Mühlemann M, Zdzieblo D, Friedrich A, Berger C, Otto C, Walles H, et al. Altered pancreatic islet morphology and function in SGLT1 knockout mice on a glucose-deficient, fat-enriched diet. Molecular Metabolism [Internet]. 2018 May 23 [cited 2025 Nov 3];13:67–76. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6026318/
  53. Ishimaru Y, Matsunami H. Transient Receptor Potential (TRP) Channels and Taste Sensation. Journal of Dental Research. 2009 Mar;88(3):212–8.
  54. Molitor EV, Riedel K, Krohn M, Hafner M, Rudolf R, Cesetti T. Sweet Taste Is Complex: Signaling Cascades and Circuits Involved in Sweet Sensation. Frontiers in Human Neuroscience [Internet]. 2021;15:667709. Available from: https://pubmed.ncbi.nlm.nih.gov/34239428/
  55. Breslin PAS, Izumi A, Tharp A, Ohkuri T, Yokoo Y, Flammer LJ, et al. Evidence that human oral glucose detection involves a sweet taste pathway and a glucose transporter pathway. Glendinning JI, editor. PLOS ONE. 2021 Oct 6;16(10):e0256989.
  56. Smith NJ, Grant JN, Moon JI, So SS, Finch AM. Critically evaluating sweet taste receptor expression and signaling through a molecular pharmacology lens. The FEBS Journal. 2021 Mar 6;288(8):2660–72.
  57. Martínez-Carrillo BE, Rosales-Gómez CA, Ramírez-Durán N, Reséndiz-Albor AA, Escoto-Herrera JA, Mondragón-Velásquez T, et al. Effect of Chronic Consumption of Sweeteners on Microbiota and Immunity in the Small Intestine of Young Mice. International Journal of Food Science. 2019 Aug 20;2019:1–16.
  58. Tellez LA, Ren X, Han W, Medina S, Ferreira JG, Yeckel CW, et al. Glucose utilization rates regulate intake levels of artificial sweeteners. The Journal of Physiology. 2013 Oct 10;591(22):5727–44.
  59. Frank GKW, Oberndorfer TA, Simmons AN, Paulus MP, Fudge JL, Yang TT, et al. Sucrose activates human taste pathways differently from artificial sweetener. NeuroImage. 2008 Feb;39(4):1559–69.
  60. Han W, Tellez LA, Niu J, Medina S, Ferreira TL, Zhang XB, et al. Striatal Dopamine Links Gastrointestinal Rerouting to Altered Sweet Appetite. 2016 Jan 12;23(1):103–12.
  61. Ivan DA. Flavor vs Energy Sensing in Brain Reward Circuits. Frontiers in Integrative Neuroscience. 2015;9.
  62. Vijay Kumar Malesu. News-Medical [Internet]. News-Medical. 2025 [cited 2025 Nov 3]. Available from: https://www.news-medical.net/news/20250330/Why-sucralose-could-make-you-hungrier-instead-of-helping-you-lose-weight.aspx
  63. Larkin M. Sucralose Affects Brain Mechanisms That Regulate Appetite [Internet]. Medscape. 2025 [cited 2025 Nov 3]. Available from: https://www.medscape.com/viewarticle/sucralose-affects-brain-mechanisms-regulate-appetite-2025a10008lu
  64. Salinas-Velarde ID, Bernal-Morales B, Pacheco-Cabrera P, Sánchez-Aparicio P, Pascual-Mathey LI, Venebra-Muñoz A. Lower ΔFosB expression in the dopaminergic system after stevia consumption in rats housed under environmental enrichment conditions. Brain Research Bulletin [Internet]. 2021 Oct 5;177:172–80. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0361923021002938
  65. Zhang X, Luo S, Jones S, Hsu E, Page KA, Monterosso JR. Impacts of Acute Sucralose and Glucose on Brain Activity during Food Decisions in Humans. Nutrients. 2020 Oct 27;12(11):3283.
  66. van Rijn I, Griffioen-Roose S, de Graaf C, Smeets PAM. Neural Processing of Calories in Brain Reward Areas Can be Modulated by Reward Sensitivity. Frontiers in Behavioral Neuroscience. 2016 Jan 14;9.
  67. Kimia Rostampour, Fatemeh Moghtaderi, Najafi A, Behnaz Seyedjafari, Amin Salehi-Abargouei. The effects of non-nutritive sweeteners on energy and macronutrients intake in adults: a grade-assessed systematic review and meta-analyses of randomized controlled trials. Frontiers in Nutrition. 2024 Nov 13;11.
  68. Wilk K, Korytek W, Pelczyńska M, Moszak M, Bogdański P. The Effect of Artificial Sweeteners Use on Sweet Taste Perception and Weight Loss Efficacy: A Review. Nutrients [Internet]. 2022 Mar 16;14(6):1261. Available from: https://www.mdpi.com/2072-6643/14/6/1261
  69. Swithers SE, Martin AA, Davidson TL. High-intensity sweeteners and energy balance. Physiology & Behavior. 2010 Apr;100(1):55–62.
  70. Rogers PJ, Hogenkamp PS, de Graaf C, Higgs S, Lluch A, Ness AR, et al. Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies. International Journal of Obesity [Internet]. 2015 Sep 14;40(3):381–94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786736/
  71. Méndez-García LA, Bueno-Hernández N, Cid-Soto MA, De León KL, Mendoza-Martínez VM, Espinosa-Flores AJ, et al. Ten-Week Sucralose Consumption Induces Gut Dysbiosis and Altered Glucose and Insulin Levels in Healthy Young Adults. Microorganisms [Internet]. 2022 Feb 1;10(2):434. Available from: https://www.mdpi.com/2076-2607/10/2/434
  72. Bian X, Chi L, Gao B, Tu P, Ru H, Lu K. Gut Microbiome Response to Sucralose and Its Potential Role in Inducing Liver Inflammation in Mice. Frontiers in Physiology. 2017 Jul 24;8(487).
  73. Zhang M, Chen J, Yang M, Qian C, Liu Y, Qi Y, et al. Low Doses of Sucralose Alter Fecal Microbiota in High-Fat Diet-Induced Obese Rats. Frontiers in Nutrition. 2021 Dec 28;8.
  74. Yang L, Wang S, Jin J, Wang J, Chen W, Xue Y, et al. Sucralose triggers insulin resistance leading to follicular dysplasia in mice. Reproductive Toxicology. 2024 Jun 14;128:108644–4.
  75. Warshaw H, Edelman SV. Practical Strategies to Help Reduce Added Sugars Consumption to Support Glycemic and Weight Management Goals. Clinical Diabetes [Internet]. 2021 Jan 1;39(1):45–56. Available from: https://clinical.diabetesjournals.org/content/39/1/45
  76. Lohner S, Kuellenberg de Gaudry D, Toews I, Ferenci T, Meerpohl JJ. Non-nutritive sweeteners for diabetes mellitus. Cochrane Database of Systematic Reviews. 2020 May 25;
  77. Suez J, Cohen Y, Valdés-Mas R, Mor U, Dori-Bachash M, Federici S, et al. Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. Cell [Internet]. 2022 Aug 17;185(18):S0092-8674(22)009199. Available from: https://pubmed.ncbi.nlm.nih.gov/35987213/