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The Tale of Two Sugars: How Fructose Drives Disease While D-Allulose Promotes Health

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Introduction

The global prevalence of metabolic syndrome, characterized by a cluster of conditions including central obesity, dyslipidaemia, insulin resistance, and hypertension, has increased in parallel with the consumption of added sugars, particularly those containing fructose [1]. Traditional nutritional paradigms have often characterized fructose as merely representing “empty calories,” but ` evidence suggests more complex biochemical interactions with specific metabolic consequences beyond its caloric content.

Fructose is a naturally occurring monosaccharide, commonly found in fruits, honey, and as a component of added sugars such a such as sucrose and high-fructose corn syrup. As a significant part of the modern diet, fructose has garnered increasing attention due to its distinct metabolic pathway and its implications for human health. Unlike glucose which is metabolized widely throughout the body and strictly regulated at key enzymatic checkpoints, fructose is predominantly metabolized in the liver. Upon absorption, fructose rapidly enters hepatocytes through specific transporters and undergoes phosphorylation by fructokinase to form fructose-1-phosphate. This process bypasses crucial regulatory steps of glycolysis, resulting in unregulated substrate flow into pathways that can lead to increased lipid synthesis and uric acid production [2-4].

Emerging research highlight that high dietary fructose intake, especially from processed foods and beverages, may be contribute to the development of metabolic disturbances such as insulin resistance, dyslipidaemia, and non-alcoholic fatty liver disease. These effects are not solely due to caloric excess, but are attributed to the unique biochemistry of fructose metabolism in humans [4-6]. Ongoing studies are exploring not only the health risk associated with excessive fructose consumption, but also the underlying molecular mechanisms, providing critical insight for dietary recommendations and therapeutic strategies in metabolic health.

Recent scientific discourse has introduced comparative analyses between fructose and its structural counterpart D-allulose (formerly D-psicose), a C-3 epimer that shares structural similarity but exhibits markedly different metabolic outcomes. This biochemical dichotomy presents a compelling framework for understanding how subtle structural differences can yield significantly different physiological consequences [7].

This review examines the biochemical mechanisms underlying fructose metabolism, with particular focus on the fructokinase-mediated pathway and subsequent uric acid production, and contrasts these with the metabolic fate of D-allulose. Understanding these differential pathways has significant implications for nutritional science, public health approaches to sugar consumption, and potential therapeutic interventions for metabolic disorders.

Fructose Metabolism: Unique Biochemical Pathway and Consequences

Fructokinase: A Critical Enzyme Without Negative Feedback

Fructose metabolism is distinct from that of glucose, primarily due to its rapid uptake by the liver and its entrance into metabolic pathways that bypass key regulatory steps. Most dietary fructose is absorbed via the intestinal GLUT5 transporter and is efficiently extracted by the liver, where it is metabolized predominantly through a sequence of reactions beginning with phosphorylation by fructokinase (ketohexokinase, KHK) [3,4,8].

Unlike glucose, which is phosphorylated by hexokinase and tightly regulated by feedback inhibition at the phosphofructokinase-1 (PFK-1) step, fructose metabolism bypasses this rate-limiting and allosterically regulated step [3,9]. This means there is minimal control over the entry of fructose into glycolytic and lipogenic pathways, allowing fructose carbons to be rapidly converted to triose phosphates and then to pyruvate, lactate, and acetyl-CoA without the physiological checks that modulate glucose metabolism [3,8,9].

Fructokinase catalyzes the first step: phosphorylation of fructose to fructose-1-phosphate using ATP. Importantly, fructokinase acts independently of cellular energy status and lacks negative feedback regulation, distinguishing it from other sugar kinases [10-12]. As a result, high fructose intake leads to rapid ATP consumption, transient intracellular phosphate depletion, and persistent flow of metabolites downstream [8,10,14].

Uric Acid Production in Fructose Metabolism

A crucial biochemical signature of fructose metabolism is the transient depletion of ATP and phosphate in hepatocytes following fructokinase activity. This prompts the activation of adenosine monophosphate (AMP) deaminase, leading to accelerated degradation of AMP to inosine monophosphate and ultimately uric acid [10,14,15]. Circulating uric acid can spike within an hour of fructose ingestion, with increases of 1-2 mg/dL observed in humans [1,10,14].

Notably uric acid is not just a byproduct but can also act to upregulate fructokinase expression through the activation of the ChREBP (Carbohydrate-Responsive Element-Binding Protein), transcription factor, further amplifying hepatic fructose metabolism and its downstream effects [10,11]. This feed-forward loop may be contribute significantly to inter-individual differences in sensitivity to fructose and susceptibility to metabolic dysfunction [11].

Hepatic Lipogenesis and Metabolic Dysfunction

As fructose metabolism bypasses glycolytic control points, it shunts excess substrates towards de novo lipogenesis (DNL)  in the liver, promoting increased synthesis of fatty acids and triglycerides [8,16]. Compared to glucose, fructose is more potent inducer of hepatic lipogenesis, as supported by both animal and human studies [16,17].

Consequences of this metabolic routing include:

  • Hepatic Steatosis (fatty liver): Fructose-induced DNL contributes to triglyceride accumulation and liver fat, central to metabolic dysfunction-associated statotic liver disease (MASLD/NAFLD) [16-18].
  • Insulin resistance and inflammation: ectopic lipid deposition activates inflammatory signalling and impairs insulin action [17,18].
  • Increased VLDL and hypertriglyceridemia: The production of triglyceride-rich VLDL particles is enhanced, promoting dyslipidaemia [10,16].
  • Hepatocellular dysfunction: Prolonged exposure to high fructose fosters mitochondrial dysfunction, ER stress, and systemic metabolic derangements [18].
FeatureFructose MetabolismConsequences
Major entry siteLiver (via GLUT 5/GLUT2)Hepatic-centric metabolism
First enzymeFructokinase (KHK), no negative feedbackRapid ATP consumption, phosphate depletion
Regulatory bypassSkips PFK-1, not regulated by ATP/CitrateUnchecked glycolytic and lipogenic flux
Uric acid productionYes, via AMP degradationPromotes KHK expression, linked to steatosis, gout
LipogenesisStrong inducer of DNL, more potent than glucoseHepatic steatosis, VLDL overproduction
Metabolic dysfunctionInsulin resistance, inflammation, mitochondrial stressMASLD/NAFLD, cardiometabolic risk
Table 1. Key Feature of Fructose Metabolism

Fructose’s unique pathway-especially the lack of feedback control at the fructokinase step and the coupling of uric acid production with lipogenesis-underlies its powerful role in the development of metabolic disorders. These features help explain why excessive dietary fructose is more strongly linked with hepatic and systemic metabolic diseases than other common dietary sugars [13,14,16,17].

D-Allulose: The Beneficial Structural Counterpart of Fructose

Structural and Metabolic Properties of D-Allulose

D-Allulose (also known as D-psicose) is a rare, naturally occurring monosaccharide, classified as a six-carbon ketohexose and C-3 epimer of D-fructose with molecular formula of C6H12O6 and molar mass of 180.16g/mol [19-22]. The key difference from D-fructose is the inversion of the hydroxyl group at the C-3 carbon. D-allulose appears as a white, odourless crystalline powder with a melting point around 96 degree celcius. Highly soluble in water (291/100g water at 20oC), and has about 70% the sweetness of sucrose but almost no caloric value (0.007-0.2kcal/g) and is largely absorbed and subsequently excreted in urine rather than being metabolized [20-22].

GLP-1 Secretion and Vagal Afferent Activation

A critical mechanism distinguishing D-allulose from fructose is its ability to stimulate glucagon-like peptide-1 (GLP-1) secretion from the gut, peaking at 30-120 min post-ingestion in animal models and humans [23-26]. Unlike glucose, D-allulose induced GLP-1 secretion is partly mediated by intestinal distension due to its slow absorption and poor metabolizability, rather than direct intracellular energy metabolism. Volumetric stimulation/intestinal stretch activates L-cells in the gut to secrete GLP-1 [24]. These characteristics leads to vagal afferent activation where D-allulose raised GLP-1 levels act on GLP-1 receptors on vagal afferent nerves, transmitting satiety and metabolic regulatory signals to the brain. Experimental models show that D-allulose’s beneficial effects on feeding behaviour, weight, and metabolic control depend on this vagal pathway, as they are blunted by vagotomy or GLP-1R blockade [24,26].

Metabolic Benefits of D-Allulose

Unlike fructose, which promotes lipogenesis and insulin resistance, D-allulose has demonstrated beneficial effects on metabolism. D-allulose has many metabolic benefits rather than fructose:

  • Glycemic control: D-allulose lowers postprandial blood glucose and suppresses increases in blood insulin after carbohydrate ingestion in both health human and those with impaired glucose tolerance [27,29,30].
  • Insulin sensitivity: Chronic intake improves insulin responsiveness of target tissues [23,27].
  • Weight management: By increasing GLP-1 and activating satiety pathways, D-allulose reduces calorie intake and supports body weight reduction and anti-obesity effects. It promotes energy expenditure by encouraging “browning” of white adipose tissue and upregulation of mitochondrial UCP-1 [23,27,28].
  • Lipid metabolism: D-allulose decreases lipogenesis in adipose tissue and liver, activates b-oxidation, and reduces markers of metabolic inflammation [22,27,28].
  • Chronotherapeutic effects: Administration of D-allulose at specific times can ameliorate arrhythmic overeating, visceral fat accumulation, and glucose intolerance, partly through GLP-1/vagal pathways [23].
  • Anti-inflammatory and antioxidant: Further physiological effects include the reduced inflammatory markers and enhanced antioxidant defenses, supporting general metabolic health [27,28].
Property/EffectsDetail
Structural classC-3 epimer of fructose (ketohexose) [19-22]
Sweetness (vs. sucrose)70%
Caloric value~0.007-0.2kcal/g
AbsorptionPartly absorbed, mostly excreted unmetabolized [20,22]
Blood glucose impactNone/negligible [20,29]
GLP-1 secretionStrongly stimulates via intestinal distension [23,24]
Vagal afferent activationYes, mediates appetite/metabolic benefits [23]
Glycaemic benefitReduces postprandial glucose/insulin [29,30]
Weight/lipid benefitLowers fat mass, enhances browning, improves lipid [23,27,28].
Table 2. Key Properties and Effects of D-Allulose

D-allulose is rare sugar with a unique structure and metabolic fate: it act as a non-caloric sweetener with minimal metabolic impact, robustly stimulates GLP-1 secretion and vagal signalling, and confers multiple metabolic benefits- including improvement in glycaemic control, weight management, lipid metabolism, and systemic inflammation- making it highly promising for managing diabetes, obesity, and metabolic syndrome [23,24,29].

ParameterFructoseD-Allulose
Hepatic UptakeGLUT2, rapidLimited
Initial EnzymeFructokinase (KHK)Minimal phosphorylation
ATP UseHigh, rapid depletionSparing
Uric AcidIncreasesNeutral
LipogenesisStimulatesAttenuates
GLP-1 SecretionSlight increaseRobust increase
Insulin ResponseModest acuteImproved sensitivity
Caloric Value~4kcal/g~0.2kcal/g
Postprandial GlycemiaTends to raiseReduces
Table 3. Comparative Physiology: Fructose Versus D-Allulose

Tissue-Specific Roles in Fructose Metabolism

Differential Functions of Intestinal and Hepatic Fructokinase

Fructokinase (ketohexokinase, KHK) is the key enzyme that initiates fructose metabolism in the body, but its actions differ significantly between the intestine and the liver.

Intestinal Fructokinase

  • Location & Function: Fructokinase is highly expressed in the small intestine, mainly in the duodenum and jejunum. After ingestion, a substantial portion of dietary fructose is metabolized here, especially when intake is physiological (not excessive). This pre-systemic metabolism limits the amount of fructose that reaches the liver in normal situations [31-33].
  • Metabolic Effects: Intestinal fructokinase converts fructose to fructose-1-phosphate using ATP. This helps regulate fructose influx to the liver and modulates local metabolic effects, such as increasing intestinal permeability and potentially contributing to endotoxemia when consumed in high amounts [32,34]. The unique activity of intestinal fructokinase can alter tight junction proteins (e.g., claudins, occluding), thereby influencing gut barrier integrity [34].
  • Role in Taste and Intake: Intestinal fructose metabolism affects sugar preference and systemic sugar intake. Mice lacking intestinal fructokinase show altered sweet taste preference and are less prone to excessive sugar consumption [33,35].

Hepatic Fructokinase

  • Location & Function: The liver expresses both KHK-C and KHK-A isoforms of fructokinase, with KHK-C being particularly active [34]. Fructose that escapes immediate intestinal metabolism is rapidly cleared by the liver, where fructokinase phosphorylates it to fructose-1-phosphate, consuming ATP as part of this reaction.
  • Bypassing Glycolytic Control: Hepatic fructokinase enables fructose metabolism to bypass phosphofructokinase, a key regulatory step for glucose. This allows a rapid and unregulated flow of fructose carbons into glycolysis and, subsequently, lipogenesis [36,37]. As a result, the liver becomes a central site for fructose-induced triglyceride and fat production, linking fructose intake to fatty liver and metabolic syndrome [33].
  • Systemic Metabolic Effects: Genetic or pharmacological blockade of hepatic fructokinase protects against fructose-induced features of metabolic syndrome, including obesity , hepatic steatosis, insulin resistance, and inflammation- even with unchanged calorie or sugar intake [33].
TissueDominant EffectFunction
IntestinePre-systemic metabolismLimits fructose load to liver, affects gut barrier, modulates sugar preference and intake [32,33,35]
LiverCentral in systemic fructose effectsRapid clearance, drives de novo lipogenesis, key in metabolic dysfunction [33,36,37]
Table 4. Comparative Summary

Uric Acid’s Role in Hepatic Metabolism

  • ATP Depletion & Uric Acid formation: During phosphorylation of fructose by fructokinase in hepatocytes, ATP is consumed rapidly, leading to transient phosphate depletion. This activates AMP deaminase, increasing AMP degradation and resulting in a rise in intracellular uric acid [14,34,38].
  • Regulation of Fructokinase Expression: Uric acid has a feedback role; it stimulates the expression of hepatic fructokinase (KHK), amplifying fructose’s effects. This is mediated by uric acid’s activation the KHK gene in hepatocytes. Inhibition of uric acid production blocks this amplification and prevents excessive lipid accumulation in the liver [14,15,38].
  • Contribution to Steatosis and Insulin Resistance: Elevated uric acid correlates with incidence and severity of non-alcoholic fatty liver disease (NAFLD). Uric acid-induced KHK upregulation increases hepatic sensitivity to fructose, promoting lipid synthesis, mitochondrial stress, and inflammatory signalling- central events in hepatic steatosis and insulin resistance [14,38].

The insights of this chapter is that intestinal fructokinase is protective at physiological intake by limiting liver exposure but with high fructose loads, both the intestine and liver contribute to adverse outcome. Hepatic fructokinase is the main driver of systemic negative metabolic consequences of fructose, due to rapid and unregulated metabolism. While uric acid acts beyond a metabolic byproduct. In the liver, it acts as a critical amplifier of fructose’s effects, upregulating fructokinase for enhanced lipogenesis, and linking fructose intake to the risk of NAFLD and metabolic syndrome [14,15,33,38].

These tissue-specific roles underscore why dietary fructose has such profound impacts on metabolic health and why targeting fructokinase or uric acid pathways presents an avenue for intervention in fructose-driven diseases.

Therapeutic Implications and Future Directions

Targeting Fructokinase and Uric Acid Production

Fructokinase Inhibition as Therapeutic Target

Fructokinase (ketohexokinase, KHK) is the first and rate-limiting enzyme in fructose metabolism, catalyzing the phosphorylation of fructose to fructose-1-phosphate. Its unregulated activity (lacking negative feedback) leads to rapid ATP depletion, uric acid generation and drives hepatic lipogenesis. Inhibiting fructokinase has been shown to:

  • Reduce hepatic steatosis and metabolic dysfunction: Pharmacological and genetic blockade of fructokinase protects against fructose-induced features of metabolic syndrome, including obesity, hepatic lipid accumulation insulin resistance, and inflammation-even when dietary fructose intake remains high [39,40].
  • Protect organ function: Fructokinase inhibition ameliorates acute kidney injury models and may help preserve kidney and liver health by reducing intracellular ARTP depletion and downstream uric acid production [40].
  • Potential cancer therapy: Some cancers, such as pancreatic cancer, have upregulated fructose metabolism. Blocking fructokinase or fructose pathways slows tumor progression and may synergize with other therapies [41,42].

Experemental agents like luteolin serve as fructokinase inhibitors in animal studies, demonstrating improved outcomes in disease models, but human data are limited and under development [39,40].

Targeting Uric Acid Production

Uric acid is produced as a byproduct of ATP degradation during fructose metabolism and plays a key role in amplifying fructose’s lipogenic effects by upregulating KHK expression via ChREBP activation. Elevated uric acid is implicated in hepatic steatosis, metabolic syndrome, and cardiovascular disease [14,43].

Therapeutic inhibition of uric acid production typically uses xanthine oxidase (XO) inhibitors, such as:

  • Allopurinol, febuxoxtat, topixosostat: These agents reduce uric acid synthesis, improve endothelial function, and decrease hepatic fat accumulation in experimental models [14,43].
  • Metabolic benefits: XO inhibitors have demonstrated improved insulin sensitivity, reduced oxidative stress, and attenuated progression of NAFLD and cardiovascular diseases [43,44].

Additionally, inhibiting AMP deaminase (which leads to uric acid formation), or blocking uric acid transporters is being studied for further benefits in reducing metabolic dysfunction associated with excessive fructose intake [43.

D-Allulose as a Therapeutic Agent

D-allulose displays unique metabolic properties:

  • Minimal metabolism and low calories: D-Allulose is poorly metabolized, is excreted in urine unchanged, and does not meaningfully increase blood glucose or insulin levels.
  • Anti-hyperglycaemic and anti-hyperlipidaemic effects: Oral D-allulose administration reduces postprandial blood glucose and insulin, improves insulin sensitivity, and lowers plasma and hepatic triglycerides in both animals and humans [27,28,45].
  • Inhibiting hepatic gluconeogenesis: it promotes hepatic glucokinase translocation and glycogen synthesis, suppresses gluconeogenesis, and decreases G6Pase activity, thereby improving hepatic glucose metabolism [28].
  • GLP-1 secretion and appetite regulation: D-Allulose robustly stimulates gut GLP-1 secretion, which activates vagal afferents, suppresses appetite, and increases energy expenditure by promoting browning of white adipose tissue [27,28].
  • Additional benefits: D-Allulose exhibits anti-inflammatory, antioxidant and anti-nephropatic effects, supporting its broader use in metabolic disease management [27,28,46].

Future Directions

Ongoing and future research priorities include:

  • Development of safe and specific fructokinase and uric acid pathway inhibitors for clinical use in NAFLD, metabolic syndrome, and potentially cancer [39,41]
  • Further elucidation of the uric acid-KHK-ChREBP axis and its role in inter-individual susceptibility to metabolic diseases, to allow for personalized therapeutic interventions [14].
  • Clinical trials for D-allulose: Large scale, long term trials to establish the efficacy, optimal dosage, and dosage, and safety of D-allulose in diverse populations, especially in those at risk for diabetes, obesity, and fatty liver disease [27,45].
  • Exploring combination therapies-such as XO inhibitors with lifestyle and dietary intervention, or combination of rare sugars and KHK inhibitors-for synergistic effects in metabolic disease prevention and treatment [27].
  • Investigating gut-liver-brain axis modulation by rare sugars lie D-allulose and its impact on satiety, energy balance, and metabolic resilience [27,28].

In summary, targeting fructokinase and uric acid production are promising strategies to blunt the adverse metabolic effects of fructose. D-allulose , as a low-calorie sugar substitute with multiple metabolic benefits, represents an emerging therapeutic agent. Future research should focus on translation to clinical practice, safety, and integration into broader metabolic disease management frameworks [14,27,40].

Recommendations for Minimizing Fructose and Incorporating Allulose for Optimal Metabolic Health

Evidence-Based Rationale for Limiting Fructose Consumption

Numerous studies have shown that excessive fructose intake- especially from added sugars in soft drinks, packaged foods, and processed snacks- is linked to increased risk for metabolic syndrome, fatty liver disease (NAFLD), insulin resistance, dyslipidaemia, and cardiovascular disease. Fructose is unique in its ability to bypass key metabolic regulatory steps in the liver, leading to unregulated lipid synthesis and increased uric acid production, both of which drive metabolic dysfunction [47-49].

Clinical and epidemiological evidence supports the following key insights:

  • Reducing fructose intake, even for a short (e.g., 9 days), can significantly lower liver fat, visceral fat, markers of insulin resistance, and improve the lipid profile [47,50].
  • High-fructose diets are associated with increased de novo lipogenesis, promoting hepatic steatosis and adverse atherogenic profiles [47,48].
  • International and national guidelines recommend limiting free sugar (including fructose) intake to less than 10% of total daily energy, with stricter thresholds for individuals with NAFLD or metabolic concerns [48,51].

Practical Recommendations for Reducing Fructose Intake:

  • Read ingredient labels: Avoid products listing “fructose”, “high-fructose corn syrup”, “glucose-fructose”, “fruit juice concentrate”, “honey”, or “agave nectar” among the top ingredients [52,53].
  • Cut back on sweetened beverages: Eliminate or drastically reduce consumption of sodas, fruit drinks, sweetened teas, and energy drinks [53].
  • Limit processed and packaged foods: Many snacks, baked goods, and cereals are formulated with added sugars high in fructose.
  • Moderate fruit juice and dried fruit intake: Opt for whole fruits, and limit portion sizes especially high-fructose fruits.
  • Distribute intake: If consuming foods with fructose, eat smaller portions spread throughout the day and pair with other foods to slow absorption [52,54]
  • Favor low-fructose alternatives: Choose vegetables, whole grains, and protein sources naturally low in fructose as dietary staples.
  • Consider a short-term fructose restriction period: Research has shown that even short periods of dietary fructose restriction can produce significant improvements in metabolic health markers.

Allulose as a Therapeutic Alternative to Fructose

Allulose (D-psicose) is a rare sugar and a C-3 epimer of fructose that tastes similar to sucrose but has negligible impact on blood glucose and insulin levels. Most consumed allulose is absorbed but not metabolized, passing through the body with almost no caloric contribution [55,56].

Evidence-Based Benefits

  • Metabolic improvement: Supplementing with allulose can reduce body weight gain, insulin resistance, hepatic triglyceride accumulation, and improve glycemic control and satiety (partly through increased GLP-1 secretion) [55,56].
  • No lipogenic stimulation: Unlike fructose, allulose does not promote de novo lipogenesis or fat accumulation in the liver [55,57].
  • Safe and well-tolerated: Human studies indicate doses of 5-10g with meals are effective for mitigating postprandial glucose and show minimal side effects (occasional mild GI discomfort at high doses) [55,56].

Recommendations for Incorporating Allulose

  • Start low, increase gradually: Begin with 5-10g of allulose per meal, as supported by evidence for metabolic benefits and glycemic control [56,58].
  • Replace added sugars: Use allulose as a direct substitute in beverages, baking, sauces, and desserts- its properties closely mimic those of table sugar, allowing for an easy 1:1 replacement in many recipes [56,57].
  • Combine creatively: Allulose can be paired with other non-nutritive sweeteners, but read labels carefully, as some blends may include sweeteners with potential adverse metabolic effects [57].
  • Watch for individual tolerance: Most people tolerate allulose well, but excessive amounts can cause mild digestive discomfort. Monitor tolerance when increasing intake [55,56].
  • Recognize product labelling: Allulose may be listed as D-psicose or pseudo-fructose. In many regions, its unique metabolism means it isn’t included in “Total Sugars” on nutrition labels [56].
Strategy/AlternativeRationale and Guidance
Limit fructoseStrongly associated with NAFLD, metabolic syndrome, CVD-aim for <10% of energy from added sugars [47,48,51].
Avoid SourcesCut sweetened drinks, processed snacks, read labels for added sugars/ high fructose ingredients [52,53].
Use AlluloseSubstitute 1:1 for sugar in recipes; 5-10g/meal shown to improve glycemic and metabolic markers [55,56].
Monitor toleranceGradually increase allulose; minimal known side effects, rare GI discomfort at high doses [56].
Table 5. Summary Table of Using Alterative Fructose

In conclusion, minimizing dietary fructose-especially from added sugars-is a key, evidence-backed strategy for reducing the risk and reversing early markers of metabolic diseases. Allulose provides a safe, functional, and palatable alternative that supports glycemic control, appetite management, and overall metabolic health, making it a valuable addition to a low-fructose, health-optimized diet [47,55,56].

Conclusion

High dietary fructose intake-especially from added sugars-has emerged as a significant contributor to the global rise in metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), insulin resistance, and cardiometabolic syndrome. Unique aspects of fructose metabolism, notably the lack of feedback regulation at the fructokinase (KHK) step and the coupling of uric acid generation and lipogenesis, underpin this risk [2-4,10-12, 14-16,38]. The roles of intestinal and hepatic fructokinase are tissue-specific: pre-systemic metabolism in the intestine can limit hepatic exposure, yet, with excessive intake, the liver rapidly metabolizes fructose, driving harmful pathways of de novo lipogenesis and uric acid production [32,33,35-37]. Uric acid acts not merely as a byproduct but as a pathological amplifier, upregulating hepatic KHK and further fuelling metabolic dysfunction.

Conversely, D-allulose a rare C-3 epimer of fructose, offers a structurally and metabolically distinct profile: it is minimally metabolized, excreted unchanged in urine, and odes not stimulate hepatic lipogenesis or uric acid production [19-22]. Recent preclinical and clinical studies show that D-allulose improves glycemic control, enhances GLP-1 secretion, promotes appetite regulation, and attenuates hepatic fat accumulation, with negligible impact on blood glucose or insulin and strong safety/tolerability profiles [22-24,27-30]. These features make D-allulose a promising therapeutic sugar substitute for both the prevention and management of metabolic diseases.

Collectively, these insights supports strong, evidence-based recommendations for minimizing fructose intake-particularly from added sugars- and suggest the integration of D-allulose as a functional alternative for optimizing metabolic health [47,48,51-56]. Furthermore, therapeutic strategies targeting fructokinase or uric acid production represent innovative approaches to disrupt the pathophysiological cascade of fructose-induced metabolic dysfunction. Continued translational research and clinical trials are warranted to define the most effective, safe, and scalable interventions.

In summary, reducing dietary fructose exposure and harnessing safe, low-calorie rare sugars like D-allulose represent actionable strategies for preventing and managing metabolic diseases linked to modern dietary patterns.

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