Keywords: Allulose, Rare Sugar Sweetener, Postprandial Glucose, GLP-1 Secretion, Insulin Resistance, Metabolic-Associated Fatty Liver Disease (MAFLD)
Reviewed by A1C Medical Team
Introduction
Metabolic syndrome is a collection of clinical conditions, which consist of hypertension, abnormal blood glucose level, abnormal lipid levels (including high triglycerides and low High Density Lipoprotein cholesterol (HDL)), and abdominal obesity. Metabolic syndrome has become a major metabolic problem, worldwide, with its continuous growing prevalence. Abnormal blood glucose and lipid levels are particularly relevant clinically to higher risk of developing chronic diseases; such as coronary arterial disease, cerebrovascular diseases, and heart failure. Globally, the prevalence of metabolic syndrome has risen from 11.9% in 2000 to 28.4% in 2021. In the same year, approximately 1.54 billion adults in the world had metabolic syndrome, with the highest absolute increase of prevalence observed in East Asia.[1] Metabolic syndrome did not only contribute to annual morbidity and mortality as a cluster of disease, but also from each individual disease. High fasting plasma glucose level (> 5.4 mmol/L) contributed to 6.5% of Disability-Adjusted Life Years (DALYs) and 2.4 million deaths yearly; while high systolic blood pressure (> 110 mmHg) also caused 218 million DALYS and 10.8 million deaths annually.[2] Additionally, high LDL level and high BMI (> 25 kg/m2) also contributed to 4.4 million deaths and 5 million deaths, respectively.[3,4] Another epidemiological study also demonstrated that the global prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) was 1.27 billion people in 2021 with continuous increment of age-standardised prevalence rate in the last twenty years with the higher burdens in low to middle sociodemographic index countries.[5] These data indicated that the burden of these diseases remains prominent and more efforts are necessary to reduce metabolic risk factors.
One of the pursuits of innovative and effective interventions for lowering health burdens due to metabolic diseases is discovering potential metabolic modulators and making them a part of a healthier lifestyle in modern societies. Nowadays, the rising number of non-communicable diseases has been associated with high consumption of refined sugar, which, unfortunately, has become an inseparable part of food cultures around the world. Refined sugar plays an important role for flavor, sweetening properties, as well as food preservation and bulking agents in our diet. However, the use of refined sugar can also increase risk of metabolic and neurodevelopmental disease, both in adults and children. Sugar can be categorized chemically into monosaccharides and disaccharides. The three main monosaccharides are glucose, fructose, and galactose; while naturally occurring disaccharides, oligosaccharides, and polysaccharides are made up by hexoses. Sugars with “exposed” carbonyl groups are referred to as non-reducing sugars or sucrose. Sucrose is more widely known as table sugar; consisting of glucose and fructose units. Table sugar is the oldest and most widely utilized caloric sweetener for home and industrial use to increase calorie intake, improve sensory effect of food, and elevate natural satisfaction of the consumers. Regrettably, excessive sugar intake can also be a vital risk of non-communicable diseases, improper oral health, and impaired cognitive abilities. Therefore, many interventions have been studied to replace refined sugars with natural sweeteners (unrefined sugars).[6,7]
Unrefined sugars are predicted to have positive dietary impact since they consist of various bioactive components, minerals, antioxidants, fibers, and phytochemicals. These characteristics, along with higher phenol and flavonoid contents, are hypothesized to be able to lower inflammation and increase endothelial functions. Natural sweeteners with well-known antioxidant characteristics include sorghum and honey. Other natural sweeteners; such as date palm and coconut; are also known to contain higher polyphenols.[6] On the other hand, increased use of non-nutritive sweeteners has also been demonstrated to replace refined sugars. Non-nutritive sweeteners consist of naturally (e.g. stevia, monk fruit extract) and artificially-produced sweeteners (e.g. aspartame, saccharine). Although they have no caloric content, the usage of non-nutritive sweeteners in humans is limited since they have higher sweetening capacity, even compared to sugar. In addition, artificially-produced non-nutritive sweeteners cannot substitute natural sugars fully since they are not completely metabolized in the human body. Several countries also banned the use of artificially-produced non-nutritive sweeteners due to possible cancer risks; thus, making the use of artificially-produced non-nutritive sweeteners still controversial. Higher level of consumer acceptability; in terms of sweetness intensity, quality, quantity, and degradability; has been demonstrated by naturally-produced non-nutritive sweeteners.[8]
Substantial contribution of high sugar diet; especially when it is combined with high fat diet; to obesity, diabetes mellitus, and MASLD leads to development of more researches on potential low-calorie sweeteners; including allulose. Allulose is a type of rare monosaccharide and a C-3 epimer of fructose with similar chemical structure to fructose, yet with different arrangement of atoms. In the human body, allulose is poorly absorbed; thus, it also has a small impact on blood glucose levels; particularly post-prandial glucose spikes. Allulose only contains approximately 0.4 calories per gram, which is lower compared to regular sugar which contains 4 calories per gram.[9,10] Possible role of allulose in modulating gut microbiota has also been studied in relation to its benefit in improving insulin sensitivity. High processed foods, as well as high sugar diets can cause harmful bacteria overgrowth. Allulose has been proposed as one of the potential gut microbiota modulators through prebiotic effects, ability to produce Short-Chain Fatty Acid (SCFA), and modulation of gut pH. Slightly lower gut pH may increase nutrient absorption and improve overall digestive function.[10] Moreover, allulose can also improve glucose control by increasing pancreatic beta cell function and hepatic glucokinase activity, as well as decreasing fat accumulation and inflammatory responses.[9,10] Allulose has also been acknowledged as safe to be utilized as sweetener by the United States Food and Drug Administration.[11] An animal study by Kamal, et al.[9] demonstrated improvement of insulin sensitivity, as well as increased insulin-stimulated AKT phosphorylation and acetyl-CoA carboxylase phosphorylation in skeletal muscle after administration of d-Allulose. Overall, all of these findings support the potential of allulose as an effective intervention for improving metabolic health, especially in insulin resistance.
Allulose and Uric Acid Reduction
The relationship between hyperuricemia and insulin resistance has considerably been studied throughout the years. Compared to other mammals, humans tend to exhibit higher uric acid levels due to the loss-of-function mutation in the genes responsible for encoding the uricase enzymes. As a breakdown product of purine metabolism, uric acid is mainly regulated by xanthine oxidase enzymes. To prevent excess in uric acid levels, humans rely on intestinal and renal secretion of uric acid. Therefore, higher than normal uric acid level can occur due to overproduction of uric acid or decreased renal or extrarenal excretion of uric acid. High intake of fructose has also been associated with rising uric acid levels. Metabolism of fructose by fructokinase can cause declined intracellular adenosine triphosphate (ATP) and increased production of intracellular uric acid levels. Intracellular uric acid can also trigger more release of mitochondrial oxidative stress; thus, leading to more stimulation of fructose production through aldolase reductase and up-regulation of fructokinase activity.[12] In addition, insulin resistance decreases renal excretion of uric acid on the proximal tubular of kidney; thus, aggravating elevated uric acid level. A retrospective case-control study by Sakalli, et al.[13] further proved this by demonstrating a statistically significant difference in the median uric acid level between insulin-resistant (5.5 mg/dl) and insulin-sensitive (4.6 mg/dl) groups. Moreover, the rate of high uric acid level (> 4.86 mg/dl) was 11.8% in those with insulin resistance; while the rate of high uric acid level in those without insulin resistance was only 5.5%. A weak positive statistical correlation was also observed between uric acid levels and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) values in this study.[13] Similar findings were also exhibited by Hu, et al.[14]; showing a significant association between uric acid increment and HOMA-IR values in newly diagnosed and drug-naive type-2 diabetes mellitus patients. The results were strengthened by application of Mendelian randomization analysis, which lowered the risk of bias from confounding factors.
As a natural sugar, allulose becomes an attractive candidate for dietary management in metabolic diseases, especially related to hyperuricemia. As has been explained above, allulose is the C-3 epimer of fructose; thus, offering the sweetness of fructose, yet without any effect on insulin or blood sugar level. Additionally, different with fructose, allulose is also not a substrate for de novo lipogenesis and does not have any inhibitory effect towards fatty acid oxidation.[15] Swapping fructose for allulose has been proposed as a way to reduce uric acid metabolism, especially since the main source of uric acid production is attributed to fructose metabolism. A systematic review and meta-analysis of prospective cohort studies by Jamnik, et al.[16] identified a significant overall relationship between fructose intake and higher risk of gout without any significant heterogeneity between studies. Another study by Teysseire, et al.[17] also showed a significant solution-by-time interaction effect of D-allulose and serum uric acid. Contrary to this finding, though, a study by Hayashi, et al.[18] demonstrated no significant effect of D-allulose to lowering uric acid level. The study, however, only used 5 grams of D-Allulose, which was 10-grams lower compared to the dose in Teysseire’s study. Nevertheless, current evidence indicated the potential advantage of allulose in lowering serum uric acid level by improving insulin sensitivity.
Allulose as a GLP-1 Enhancer
Throughout the decades, Glucagon-like Peptide-1 (GLP-1) receptor and its agonists have obtained huge attention in the medical community; particularly related to its role in improving blood sugar levels and lipid metabolism. GLP-1 itself is a peptide, which is generally synthesized from cleaving proglucagon. GLP-1 is mainly produced in the pancreatic islet alpha-cells, intestinal mucosal (enteroendocrine) L-cells, and nerve cells in the nucleus of the solitary tract. GLP-1 is secreted in the distal jejunum, ileum, and colon as a response to nutrient intake and neuroendocrine stimulation. Meanwhile, GLP-1 receptors are members of the G-protein-coupled receptors (GPCR) family with specific affinity to GLP-1. The GLP-1 receptor is located on the cellular membrane of various cell types of the human body. The application of GLP-1 receptor agonists (GLP-1RAs) is similar to the mechanism of action of endogenous GLP-1; in which they will activate GLP-1 receptors. Consequently, insulin secretion will be enhanced, glucagon release will be inhibited, gastric emptying will be delayed, and food intake will be decreased through suppression of central appetite.[19,20]
GLP-1 is a vital incretin hormone; therefore, it influences the functionality of pancreatic alpha-cells and beta-cells prominently. GLP-1 stimulates glucose-dependent insulin secretion, as well as induces proliferation and reduces apoptosis of pancreatic beta cells. Molecularly, GLP-1 also activates the cAMP response element-binding protein (CREB), which is a critical transcription factor for insulin gene expression. In addition, GLP-1 also triggers activation of PKA enzymes through cAMP-dependent pathways. PKA is an enzyme which phosphorylates many target proteins involved in insulin synthesis and secretion. GLP-1 also maintains pancreatic beta-cell survival and proliferation through PI3k-Akt signal transduction. Benefit of GLP-1 in reducing blood sugar levels also arise from its function in inhibiting glucagon release from alpha-cells; thus, also inhibiting hepatic gluconeogenesis. GLP-1 can inhibit glucagon release from alpha-cells by directly binding to the receptors on the surface of pancreatic alpha-cells or by stimulating pancreatic beta-cells to release more insulin. Higher amounts of insulin will induce a negative feedback mechanism; thus, lowering the amount of glucagon secreted by alpha cells. In addition, GLP-1 can also bind to GLP-1 receptors on delta cells and promote secretion of somatostatin, which is a potent inhibitory hormone acting directly on neighboring alpha-cells to block glucagon secretion. Also, by interacting with GLP-1 receptors in the hypothalamus, GLP-1 can activate specific neurons which increase satiety (POMC/CART neurons) and reduce hunger (NPY/AgRP neurons) in humans. GLP-1 is also able to gastric emptying by binding to its receptors on smooth muscles and vagus nerve in the gastrointestinal tract. Through binding to its receptors on the gastrointestinal tract, GLP-1 can reduce gastric muscle contraction and prolong food retention in the gaster. Slower gastric emptying can increase satiety and stabilize post-prandial blood glucose levels.[19,20]
As one of the potential replacements of dietary sugar, in terms of anti-obesity and anti-diabetes effects, allulose has also been proposed as a way to stimulate GLP-1 secretion. An animal study by Cayabyab, et al.[15] showed that, in comparison to standard diet, groups treated with allulose had higher serum levels of the active GLP-1. The increment in serum GLP-1 levels also had a lingering effect, well past the point of administration. This result was in line with other findings of this study, which demonstrated increased glucose tolerance and reduced weight gain. Another study in mice also showed that sub-chronic administration of allulose can ameliorate metabolic dysfunction induced by ovariectomy and sucrose intake. Additionally, these effects were also suggested as being mediated by GLP-1 receptors since the experiment was performed in GLP-1 receptor knockout mice. Ovariectomy-induced metabolic dysfunction itself may occur since estrogen is also one of the regulators of GLP-1 synthesis and secretion in the pancreas and intestine, as well as highly variable anorexigenic and weight-reducing effects of GLP-1Ras in the estrous cycle, depending on the variability in circulating estrogen levels. Therefore, this result indicated that administration of allulose may mitigate the glucose metabolic problems by improving GLP-1/GLP-1 receptor-mediated control under conditions of estrogen deficiency.[21]
Allulose and Weight Loss Enhancement
Being a potentially healthy sugar substitute, allulose has also been a way to tackle the difficulty in achieving weight loss through various mechanisms. As a hallmark of metabolic syndrome, obesity has become a leading cause of morbidity with its heterogeneous related complications; starting from inducing abnormal body metabolism to physical appearance problems. Sugar substitutes, including allulose, have received more attention to solve problems attributed to obesity. Allulose has 70% of the sweetness of sucrose with nearly zero calories; thus, making it a potential substitute for obese patients. Allulose can also be produced in large quantities from hydrolyzed sucrose or isomerized D-glucose through enzymatic methods. Although acting similarly with D-glucose, D-allulose can increase glucose uptake from liver and withhold lipogenesis process in the liver. D-allulose can also reduce food intake and increase energy expenditure, as well as soleus muscle lipoprotein lipase activity. In addition, D-allulose can also inhibit fat absorption in small intestine and elevate beta-oxidation in the fat tissue.[22,23]
Various studies in animals have highlighted the benefit of allulose administration for weight loss management. A study with mice by Han, et al.[23] demonstrated that 5% D-allulose supplementation dramatically lowered body weight and fat-pad mass in mice with a high fat diet. Moreover, simultaneous decline in plasma leptin and resistin concentrations was also observed in the subjects. Further downregulation of fatty acid synthase and beta-oxidation activities was also enhanced by D-allulose administration. Taken together, the study findings also suggested the role of allulose in normalizing lipid metabolic status through inhibition of intestinal lipid absorption; resulting in reduced availability for formation of chylomicron. Additionally, allulose has also been proposed as the reason behind increased use of free fatty acids in adipose tissue towards beta-oxidation by restricting its utilization for triglyceride synthesis and formation of lipid droplets. Eventually, all of these processes can also reduce body fat and adipocyte size.[23] A newer study conducted in diet-induced obese mice showed that, compared to oral semaglutide, administration of allulose reduced feeding faster. Meanwhile sub-chronic administration of allulose was also demonstrated to significantly decrease body weight and food intake. Interestingly, although the reduction of food intake was higher in oral semaglutide group in the early period (until three days after administration), sub-chronic administration of d-allulose appeared to maintain the reduction of food intake and body weight in the late period (4-10 days) and after the treatment had been stopped. These results were thought to be related with weight reduction mechanisms of both semaglutide and allulose through the central nervous route. While both semaglutide and allulose can similarly activate anorexigenic leptin-responsive neurons, allulose can be considered more superior since it also inhibits orexigenic ghrelin-responsive neurons in the hypothalamic arcuate nucleus.[24]
Findings from animal studies evaluating the role of allulose in improving body weight have also been validated by human studies. A preliminary study in 121 Korean patients with inclusion criteria of overweight and obese nutritional status also showed the benefit of 12-weeks D-allulose supplementation by demonstrating a statistically significant metabolic improvement. Significant reduction was not only observed in body mass index, body fat mass, and body fat percentage, but also total abdominal fat area measured by Computed Tomography (CT) scan. Improvement of plasma lipid profiles (triglyceride, total cholesterol, and Low Density Lipoprotein (LDL)) was also noted from the study.[25] A randomized single-blind study by Kimura, et al.[26] also highlighted the potential of allulose as anti-obesity sweetener in humans through significantly higher post-prandial fat oxidation and significantly lower carbohydrate oxidation compared to aspartame. This result indicated the possible role of allulose to control body weight through increased energy metabolism in humans.
Allulose and Protection Against Fatty Liver
Although it has been proposed as exerting anti-inflammatory properties and able to inhibit lipid synthesis, the efficacy of allulose in managing fatty liver is still being studied. MASLD itself has been identified as having a close relationship with metabolic syndrome. Furthermore, MASLD has also been recognized as a major risk factor for progression of liver disease to cirrhosis and hepatocellular carcinoma. As a ketohexose monosaccharide which is known to substitute sucrose, several health benefits to fatty liver through its anti-inflammatory, antioxidant, regulation of glucose and lipid metabolism, as well as its neuroprotective effects.[27] An animal study by Han, et al.[21] demonstrated that liver synthesis of free fatty acids and triglycerides is lower in groups administered with allulose compared to groups receiving D-fructose, D-glucose, and erythritol. This process was further elucidated by decreased activity of Fatty Acid Synthase (FAS) and Phosphatidate Phosphatase (PAP). Aside from FAS, supplementation of allulose was also shown to down-regulate the expression of other genes involved in fatty acid synthesis and oxidation in the liver; such as ACC1, CPT1-alpha, and CPT2. Intriguingly, the decline of CPT1-alpha and CPT2 mRNA expression, as well as the increment of ACC2 mRNA expression in the liver were consistent with the decline in hepatic beta-oxidation process. Eventually, hepatic droplet lipid accumulation and secretion of Very Low Density Lipoprotein (VLDL) were also diminished in groups treated with allulose.[23]
More recent evidence from animal studies further elucidated the role of allulose supplementation in alleviating fatty liver disease, especially through its anti-inflammatory and antioxidant properties. A study by Tan, et al.[27] in 2025 showed that administration of high-dose (5% of D-allulose) and low-dose (2.5% of D-allulose) allulose in Non-Alcoholic Fatty Liver Disease (NAFLD) mouse model (induced by high fat diet) significantly reduced hepatic lipid accumulation. Groups treated with allulose also exhibited significantly lower total cholesterol, triglycerides, and LDL cholesterol levels. In addition, groups treated with high-dose allulose also demonstrated significantly higher High Density Lipoprotein (HDL) levels, accompanied with diminished oxidative stress and malondialdehyde levels in serum. Molecularly, groups treated with high-dose allulose also showed significantly decreased Receptor for Advanced Glycation End Products (RAGE) expression and NF-kB p65 protein phosphorylation in the liver. RAGE itself is a new pattern recognition receptor with a prominent role in the pathogenesis of various metabolic disorders, including diabetes mellitus. Moreover, high-dose allulose also significantly improved gut microbiota dysbiosis; indicated by increase of Patescibacteria, Firmicutes, and Actinobacteria with prominent reduction of Bacteroidetes, Verrucomicrobia, and Deferribacteres. Gut dysbiosis itself has also been recognized as a notable risk factor of progression in NAFLD. This study also demonstrated that administration of allulose yielded significant restorative effects on serum metabolomic alterations in mice with NAFLD. Attenuation of NAFLD progression was assumed to be mediated by glutathione, arginine, and proline metabolism, as well as27 Another study by Yamazaki, et al.[28] evaluated the possible role D-allulose in decreasing diet-induced fat accumulation in the liver associated with hepatic Peroxisome Proliferator-Activated Receptor Gamma (PPAR-gamma) and CD36 expression in mice. The findings showed that, based on histological analysis of stained liver tissues, 5% D-allulose solution intake lessened major hepatic abnormalities with significantly lower hepatic triglyceride content. Furthermore, allulose administration was associated with significant reduction in expression levels of PPAR-gamma and CD36 in the liver, contributing to the suppression of diet-induced hepatic lipid accumulation. Suppression of PPAR-gamma was thought to be related with higher expression of miR-130a and miR-130b.[28] Another study by Kanasaki, et l.[29] in Wistar rats also emphasized hepatic metabolomics profile after administration of D-allulose. The results showed that, after supplementation of 3% D-allulose for one month, there was improvement of metabolites regulation; particularly metabolites involved in cholesterol, bile acid, and fatty acid beta-oxidation. There was a significant modulation of metabolites related to glucuronic acid/xylulose pathway, lower levels of ascorbic acid and its metabolites, as well as lower levels of 6-phospogluconolactone, which is also a biosynthesis product from beta-d-glucose-6-phosphate. Moreover, significantly more abundant S-adenosylmethionine was also observed in the study. Significant reduction of substances which may worsen cholesterol homeostasis in the liver, such as trimethylamine N-oxide, was also seen.[29]
Recent findings also showed possible superior effects of D-allulose in attenuating progression of fatty liver in comparison to other therapeutic options, including other sugar alternatives. A study in Wistar rats also tried to compare metabolic effects of allulose and stevia. The findings indicated that allulose has a more protective effect on hepatic outcomes; shown by lack of development of fatty liver, as well as less hepatic hypertrophy. On top of that, only groups treated with stevia showed elevations in liver function tests.[15] Another in-vitro study by Warda, et al.[30] using HepG2 cells also demonstrated similar effects between D-allulose and gemfibrozil on lipid content through elevated oleic acid beta-oxidation, PPAR-alpha expression and its dependent genes which are involved in fatty acid beta-oxidation. In addition, both D-allulose and gemfibrozil were also able to increase PPAR-alpha reporter gene expression and phosphorylation which were both inhibited by the Mitogen Activated Protein (MAP) kinase inhibitor in HepG2 cells. All of these findings further validated similar insulinomimetic and anti-inflammatory effects of D-allulose and gemfibrozil in steatohepatitis.[30]
Allulose and Blood Glucose Regulation
The role of allulose in alleviating metabolic diseases is inseparable with its impact on blood glucose regulation. Having similar appearance and taste to sucrose, allulose has been proposed as a potentially healthier sweetener replacement since it has an extremely low-calorie count; only ranging from 0 to 0.39 kcal/gram, which is also way below the caloric value of typical sugars (4 kcal/gram). Allulose itself is also notable for its minimal impact on blood glucose and insulin through various mechanisms. Previous studies highlighted the ability of allulose to inhibit alpha-glucosidase activities, which consequently lead to restriction of glycemic response following carbohydrate intake. Allulose has also been demonstrated as the reason behind increased hepatic synthesis of glycogen; thus, also stimulating faster restoration of glycogen in the liver and muscle after physical activity. Regulation of glucose by allulose can also be achieved through inducing GLP-1 release from intestinal L-cells. Improvement of insulin resistance by allulose can also be obtained by decreasing triglycerides accumulation in the skeletal muscle. An animal study conducted by Kamal, et al.[31] showed that administration of 5% D-allulose attenuated insulin resistance, measured by glucose infusion rate achieved at steady state upon hyperinsulinemic euglycemic clamp test, in Wistar rates with high fructose diet. In addition, groups treated with D-allulose also demonstrated significantly lower triglyceride levels in liver, plasma, and muscle. In this study, improved skeletal muscle insulin sensitivity was also exhibited through significant increment of insulin-stimulated phosphorylation of Akt at Ser473 and phosphorylation of AMP-activated protein kinase alpha at Thr172. All of these findings further clarified positive impact of allulose administration on blood glucose regulation, especially in population with high-fructose diet.[31]
The role of allulose in improving blood glucose regulation by targeting fructose has yielded significant attraction due to various reasons. As a prevalent dietary sugar, fructose is strongly associated with more adverse metabolic outcomes. Dietary fructose can increase intestinal cell survival and intestinal villus length. As a result, there will also be greater nutrient absorption and adiposity. Metabolism of fructose is also closely related to liver steatosis, including triglycerides accumulation in the liver. Compared to glucose, fructose has also been more frequently associated with glucose tolerance, obesity, and hepatomegaly. Impaired triglycerides clearance can also be induced post-prandial lipidemia attributed to co-administration of fructose and triglycerides. Allulose can also tackle this problem by reducing triglycerides level in muscle. As a C3-epimer of fructose, D-allulose can inhibit fructose absorption in the intestine competitively, as well as reduce intestinal triglycerides absorption. Both of these processes contribute to decrease in triglycerides accumulation. Additionally, as a replacement of sweetener with extremely low-calorie count, D-allulose can also increase fatty acid oxidation; possibly through phosphorylation of Acetyl-CoA carboxylase. Another potential mechanism of D-allulose for caloric restriction mimetic is by modulating glycolysis. Therefore, diet-related metabolic adverse outcomes induced by high-sucrose and high-fat diet can possibly be ameliorated with administration of D-allulose.[31-34]
Previous studies have further validated the efficacy of allulose in lowering plasma glucose level in humans, regardless of them having diabetes mellitus or not. The results of a prospective, randomized, double-blind controlled trial in 30 study participants without diabetes mellitus. who had received 50 grams of sucrose load, showed that administration of D-allulose yielded statistically significant association with dose-dependent decrease of post-prandial plasma glucose at 30 minutes, in comparison to placebo. Lower insulin levels trend and lower insulin excursion were also observed after administration of D-allulose with the 10 grams dose. Both effects were also recognized as dose-dependent. These effects also appeared to be consistent in white and African-American population. Overall, this trial suggested that adding 10 grams of D-allulose to 50 grams of sucrose was adequate to lower post-prandial hyperglycemia caused by standard sugar load as early as at 30 minutes after administration.[35] A meta-analysis performed by Tani, et al.[36] also verified similar findings by showing that intake of 5-10 gram of allulose was able to lower post-prandial blood glucose levels in healthy humans. This study also proposed the possibility of different effect sizes for the post-prandial blood glucose lowering in accordance with the dose difference of allulose. Considerations might also be taken into effects of different timing of consumption, as well as the ratio of allulose in each meal.[36] More recent meta-analysis by Ayesh, et al.[37] in patients with type 2 diabetes mellitus showed that there was a significant reduction of post-prandial plasma glucose after administering of allulose with range of doses between 5 and 8.5 grams. Moreover, allulose also was suggested to be able to stabilize blood glucose longer since a significant decrease of Time Above Range was observed. Time Above Range itself is a glycemic metric to quantify hyperglycemic exposure risk, which is significantly related to increased risk of hyperglycemia. No statistically significant decrease, though, was found in both insulin reduction and fasting plasma glucose. These results indicated that the biggest impact of allulose was exhibited in rapid absorption and insulin-mediated clearance, contributing to its more prominent effect on post-prandial blood glucose. Meanwhile, less conspicuous effect of allulose on fasting blood glucose was possibly attributed to less sensitivity of basal insulin dynamic and hepatic gluconeogenesis process towards short-term dietary allulose intake. Improvement of post-prandial control might also be affected by the ability of allulose to increase hepatic glucokinase activity, which further enhance glycogen storage over glucose release.[37]
Conclusion
In the midst of rising overconsumption of high-sugar and high-fat diets, accordingly, the number of metabolic non-communicable diseases has also been increasing. Higher sugar intake has also been affiliated to various detrimental metabolic and inflammatory responses. Demands for healthier diets, including healthier sugar replacements, have also been augmented. Public demand specifically focuses on sugar replacement with compatible taste, excellent solubility, low energy density, and durable stability with minimal-to-none safety issues and caloric contribution. Notable attention has been received by D-allulose in recent years, which is the epimer of fructose at the third carbon position, as one of the potential alternative sweeteners. Accumulating evidence has demonstrated various beneficial effects of allulose on human health; including attenuating high blood glucose and lipid, as well as improving weight loss and hindering progression of metabolic-associated fatty liver diseases. Allulose has also been proven to be able to enhance endogenous GLP-1 secretion and regulate intestinal transcriptomes. Further in-depth studies, however, are still necessary to evaluate other physiological functions of allulose which may support its utilization in pharmaceuticals and health nutrients. Additionally, continuous identification of advancement in improving the efficiency and stability of allulose through metabolic engineering and synthetic biology through interdisciplinary collaboration and innovation can also be an attractive future field of study.
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