Medical applications of rare sugars: The potential of D-allulose in the treatment of diabetes and obesity
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Source: Gycoforum June 2, 2025.
Kensaku Fukunaga:
Medical Applications of Rare Sugars: The Potential of D-Allulose in Managing Diabetes and Obesity
Dr. Kensaku Fukunaga
Assistant Professor, Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University
Dr. Fukunaga graduated from the Faculty of Medicine, Kagawa University in 2009 and completed his four-year doctoral course at the Graduate School of Medicine, Kagawa University in 2018. He specializes in endocrinology and metabolism, participating in both clinical practice and research.
His research focuses on the clinical application of rare sugars in the context of adipose tissue, obesity, and glucose metabolism; new treatment strategies for patients with type 2 diabetes complicated by metabolic dysfunction-associated steatotic liver disease (MASLD); identification and evaluation of predictive factors for lifestyle diseases using health checkup data; and the implementation of problem-solving, experiential learning programs ("Future Classroom") aimed at preventing lifestyle diseases in children. All these efforts are directed towards clinical research for social implementation.
He is a board-certified member of the Japanese Society of Internal Medicine (JSIM), a Fellow of the JSIM (FJSIM), a physician designated for fellowship training by the JSIM, a diabetologist and consulting diabetologist of the Japan Diabetes Society, a board-certified endocrinologist and certified endocrine instructor of the Japan Endocrine Society, and an industrial physician of the Japan Medical Association.
Introduction
Diabetes and obesity-related metabolic disorders pose a significant global health burden, highlighting the need for innovative therapeutic strategies.
The cornerstone of managing these conditions involves lifestyle modifications, including diet and exercise.
Excessive sugar intake, driven by modern dietary habits, has been linked to the increasing prevalence of diabetes, obesity, and cardiovascular diseases. (Reference 1.)
This has sparked interest in safer sugar alternatives.
While artificial sweeteners have been explored for their potential benefits in obesity and diabetes management (Ref 2.),
some studies suggest they may adversely affect glucose metabolism (R 3.), necessitating a careful evaluation of their use.
D-allulose, a naturally occurring rare sugar, has garnered attention as a promising alternative.
Our clinical research suggests that D-allulose may improve glucose metabolism in patients with type 2 diabetes.
This review summarizes current evidence regarding D-allulose's effects on diabetes, obesity, and fat metabolism, and assesses its potential for clinical application.
2. Rare Sugars and D-allulose: An Overview
2-1. Definition of Rare Sugars
Rare sugars are monosaccharides and their derivatives found in limited quantities in nature.
Research has identified numerous biological activities associated with these sugars, suggesting potential health benefits.
2-2. Characteristics of D-allulose
D-allulose is a rare, low-calorie sugar (0.4 kcal/g). Although it is absorbed into the bloodstream, a significant portion is excreted in urine, minimizing its role as an energy source. (4.)
While excessive intake may cause mild gastrointestinal symptoms, the no-observed-adverse-effect level (NOAEL) is 0.55 g/kg body weight per day5, indicating that D-allulose is generally safe when consumed within recommended limits.
3. Mechanisms of D-allulose's Glycemic and Anti-Obesity Effects
3-1. Mechanism of Glycemic Control
D-allulose reduces postprandial glucose levels through multiple pathways.
In the small intestine, it inhibits α-glucosidase activity, thereby reducing glucose and fructose absorption. (6.)
In the liver, it enhances glucokinase expression, promoting glycogen synthesis while suppressing gluconeogenesis and hepatic glucose output, leading to improved glycemic control. (7.)
Additionally, D-allulose may improve insulin sensitivity and exert a protective effect on pancreatic β-cells. (8.)
Together, these mechanisms suggest its multifaceted role in glucose regulation.
3-2. Mechanism of Anti-Obesity Effects
D-allulose may aid in weight management by modulating appetite and energy metabolism. It has been shown to enhance glucagon-like peptide-1 (GLP-1) secretion, which reduces appetite via vagal afferent signaling to the hypothalamus.
Furthermore, there is growing evidence that D-allulose promotes the browning of white adipose tissue, which is associated with increased thermogenesis and energy expenditure.
This browning effect is linked to the upregulation of uncoupling protein 1 (UCP-1), a key regulator of mitochondrial heat production.
These findings suggest that D-allulose may contribute to fat reduction through several metabolic pathways, warranting further investigation.
4. Effects of D-allulose in Humans
4-1. Effect on Postprandial Glucose Levels in Healthy and Pre-diabetic Individuals
Human studies have demonstrated that D-allulose reduces postprandial glucose levels in both healthy individuals and those with impaired glucose tolerance.
In healthy subjects, D-allulose dose-dependently reduces postprandial glucose levels while also modulating insulin secretion. (10-12.)
In individuals with impaired glucose tolerance (pre-diabetes), consumption of 5 g of D-allulose with a test meal (425 kcal: 84.5 g carbohydrates, 13.3 g protein, 3.7 g fat) significantly reduced postprandial blood glucose levels. (13.)
These findings highlight D-allulose as a potential dietary intervention for improving glucose regulation.
4-2. Effects in Type 2 Diabetes Patients: A New Dietary Approach
To assess its clinical utility, we investigated the integration of D-allulose into dietary therapy for diabetes
(14.)
Our study compared a conventional diabetic diet – where calorie intake was calculated based on body weight and physical activity – with a modified diet incorporating 8.5 g of D-allulose per meal, maintaining identical macronutrient and calorie composition.
The D-allulose-enriched diet showed superior postprandial glucose suppression in patients with type 2 diabetes (Figure 1).
This study, which was the first to use continuous glucose monitoring (CGM) to evaluate the application of D-allulose in dietary therapy, supports its potential as an innovative nutritional strategy in diabetes management.
Figure 1. Effect of a D-allulose-containing diabetic therapeutic diet on postprandial blood glucose suppression
This graph shows the changes in blood glucose levels in patients with type 2 diabetes following consumption of a conventional diabetic diet (dashed line) and a D-allulose-containing diabetic diet (solid line).
The D-allulose-containing diet significantly reduced the postprandial rise in blood glucose after breakfast, lunch, and dinner.
4-3. Global Burden of Diabetes and the Potential of Rare Sugars in Asia
The U.S. Food and Drug Administration (FDA) has granted D-allulose "Generally Recognized as Safe" (GRAS) status, highlighting its safety as a food ingredient.
The global prevalence of diabetes is increasing, with Asia experiencing particularly rapid growth.
In Malaysia, for example, the incidence of diabetes is steadily rising.
A significant challenge is Ramadan, where Muslim patients fast from dawn to sunset (approximately 13 hours).
This fasting period carries the risk of daytime hypoglycemia, while Iftar, the meal after sunset, often leads to excessive food intake and an increased risk of postprandial and nocturnal hyperglycemia.
To address this problem, we conducted a study on patients with type 2 diabetes during Ramadan, investigating the effect of D-allulose on glycemic fluctuations using CGM. (15.)
The results showed a significant reduction in postprandial glucose peaks and the incremental area under the glucose curve (iAUC) after Iftar.
These findings suggest that D-allulose may help improve glycemic control during Ramadan (Figure 2).
This research highlights the potential of D-allulose as a new dietary intervention in diabetes management, especially in culturally specific settings where fasting-induced glycemic fluctuations pose a significant health risk.
Figure 2. Postprandial blood glucose lowering effect of D-allulose after Iftar
(a) D-allulose reduced postprandial peak blood glucose after Iftar.
(b) The incremental area under the blood glucose rise curve (iAUC) was significantly reduced.
5. Future Directions and Challenges
D-allulose represents a promising dietary strategy for managing diabetes and obesity, given its ability to reduce postprandial glucose levels, enhance GLP-1 secretion, and promote fat burning.
As a naturally occurring, low-calorie sugar offering potential metabolic benefits, it aligns with modern consumer preferences for healthier alternatives.
Further clinical research is needed to validate its therapeutic efficacy.
Rigorous studies assessing its long-term metabolic effects will be crucial for advancing its medical applications and integrating D-allulose into evidence-based dietary strategies for diabetes and obesity management.
References
1. Imamura F, O'Connor L, Ye Z, Mursu J, Hayashino Y, Bhupathiraju SN et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. BMJ. 2015 Jul;351:h3576.
2. Gardner C, Wylie-Rosett J, Gidding SS, Steffen LM, Johnson RK, Reader D et al. Nonnutritive Sweeteners: Current Use and Health Perspectives: A Scientific Statement From the American Heart Association and the American Diabetes Association. Diabetes Care. 2012 Aug;35(8):1798–808.
3. 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. 2022 Sep;185(18):3307-3328.e19.
4. Tsukamoto I, Hossain A, Yamaguchi F, Hirata Y, Dong Y, Kamitori K et al. Intestinal absorption, organ distribution, and urinary excretion of the rare sugar D-psicose. Drug Des Devel Ther. 2014 Oct;8:1955–64.
5. Iida T. Estimation of the No-Observed-Adverse-Effect Level of D-Psicose for Inducing Diarrhea in Humans. J Advd Food Ingred. 2007;10:15–19.
6. Hishiike T, Ogawa M, Hayakawa S, Nakajima D, O'Charoen S, Ooshima H et al. Transepithelial transport of rare sugar D-psicose in the human intestine. J Agric Food Chem. 2013 Jul;61(30):7381–6.
7. Shintani T, Yamada T, Hayashi N, Iida T, Nagata Y, Ozaki N et al. Rare sugar syrup containing d-allulose, but not high-fructose corn syrup, maintains glucose tolerance and insulin sensitivity in Wistar rats, partly via hepatic glucokinase translocation. J Agric Food Chem. 2017 Apr;65(13):2888–94.
8. Hossain A, Yamaguchi F, Hirose K, Matsunaga T, Sui L, Hirata Y et al. Rare sugar D-psicose prevents the progression and development of diabetes in the T2DM model, Otsuka Long-Evans Tokushima Fatty rats. Drug Des Devel Ther. 2015 Jan;9:525–35.
9. Iwasaki Y, Sendo M, Dezaki K, Hira T, Sato T, Nakata M et al. GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose. Nat Commun. 2018 Jan;9(1):113.
10. Yuma T, Tokuda M, Nishimoto N, Yokoi H, Izumori K. Allulose for reducing postprandial blood glucose in healthy individuals: A systematic review and meta-analysis. PLoS One. 2023 Apr;18(4):e0281150.
11. Buranapin S, Kosachunhanan N, Waisayanand N, Yokoi H, Tokuda M. Co-administration of D-allulose with sucrose beverage on glucose tolerance and insulin levels in Thai healthy volunteers. J Nutr Sci Vitaminol. 2024;70(3):203–9.
12. Franchi F, Yaranov DM, Rollini F, Rivas A, Rivas Rios J, Been L et al. Effects of D-allulose on glucose tolerance and insulin response to a standard oral sucrose load: results of a prospective, randomised, crossover study. BMJ Open Diabetes Res Care. 2021 Feb;9(1):e001939.
13. Hayashi N, Iida T, Yamada T, Okuma K, Takehara I, Yamamoto T et al. Study on the postprandial blood glucose suppression effect of D-psicose in borderline diabetes and the safety of long-term ingestion in healthy humans. Biosci Biotechnol Biochem. 2010;74(3):510–9.
14. Fukunaga K, Yoshimura T, Imachi H, Kobayashi T, Saheki T, Sato S et al. Pilot Study of the Efficacy of a Rare Sugar D-Allulose-Containing Diabetic Diet for Patients with Type 2 Diabetes: A Prospective, Randomized, Single-Blinded, Crossover Study. Nutrients. 2023 Jun;15(12):2802.
15. Japar S, Fukunaga K, Kobayashi T, Imachi H, Sato S, Saheki T et al. Pilot study on the effect of D-allulose on postprandial glucose levels in patients with type 2 diabetes during Ramadan fasting. Diabetol Metab Syndr. 2022 Jun;14(1):86.
