Medical applications of rare sugars: The potential of D-allulose in the treatment of diabetes and obesity

Source: Glycoforum

June 2, 2025

Kensaku Fukunaga:

Medical applications of rare sugars: The potential of D-allulose in the treatment of diabetes and obesity

Dr. Kensaku Fukunaga

Assistant Professor, Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University

Dr. Fukunaga graduated from Kagawa University School of Medicine in 2009 and completed his four-year doctoral training at Kagawa University Graduate School of Medicine in 2018. His specialty is endocrinology and metabolism, and he is involved 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; novel treatment strategies for patients with type 2 diabetes who are associated with metabolic dysfunction-associated fatty liver disease (MASLD); identifying and assessing predictors of lifestyle diseases using health surveillance data; and implementing problem-solving, experiential learning programs (“Future Classroom”) aimed at preventing lifestyle diseases in children. All of these efforts are directed towards clinical research for social implementation.

He is a qualified member of the board of directors of the Japanese Society of Internal Medicine (JSIM), a member of the JSIM (FJSIM), a physician appointed for fellowship training by the JSIM, a diabetologist and consultant diabetologist of the Japanese Diabetes Society, a qualified endocrinologist and certified endocrine instructor of the board of directors of the Japanese Endocrine Society, and a company physician of the Japanese Medical Association.

Introduction

Diabetes and obesity-related metabolic disorders represent a significant global health burden, highlighting the need for innovative therapeutic strategies.

The cornerstone of treating these conditions is lifestyle changes, including diet and exercise.

Excessive sugar intake driven by modern eating habits is associated with the increasing incidence of diabetes, obesity, and cardiovascular disease. (Reference 1.)

This has sparked interest in safer sugar alternatives.

While artificial sweeteners have been studied for their potential benefits in the treatment of obesity and diabetes (Ref 2.)

some studies suggest that they may adversely affect glucose metabolism (R 3.), which requires careful evaluation of their use.

D-Allulose, a naturally occurring rare sugar, has received 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 the current evidence on the effects of D-allulose on diabetes, obesity, and fat metabolism, and assesses the potential for its clinical application.

2. Rare Sugars and D-Allulose: An Overview

2-1. Definition of rare sugars

Rare sugars are monosaccharides and their derivatives that occur in limited quantities in nature.

Research has identified several biological activities associated with these sugars, suggesting potential health benefits.

2-2. Properties of D-allulose

D-Allulose is a rare, low-calorie sugar (0.4 kcal/g). Although it is absorbed into the bloodstream, most of it is excreted in the urine, minimizing its role as an energy source. (4.)

Although excessive intake may cause mild gastrointestinal symptoms, the maximum 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 glycemic and anti-obesity effects of D-allulose

3-1. Mechanism of glycemic control

D-allulose reduces postprandial glucose levels through several pathways.

It inhibits the activity of α-glucosidase in the small intestine, thereby reducing the absorption of glucose and fructose. (6.)

It increases glucokinase expression in the liver, promoting glycogen synthesis while inhibiting gluconeogenesis and hepatic glucose release, leading to better glycemic control. (7.)

Additionally, D-allulose may improve insulin sensitivity and have 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 increase the secretion of glucagon-like peptide-1 (GLP-1), which reduces appetite via vagal afferent signaling to the hypothalamus.

Furthermore, growing evidence suggests that D-allulose promotes the conversion of white adipose tissue to beige adipose tissue, which is associated with increased thermogenesis and energy expenditure.

This beige effect is associated with the upregulation of uncoupling protein 1 (UCP-1), a key regulator of mitochondrial heat production.

These results suggest that D-allulose may contribute to fat reduction through multiple metabolic pathways, which warrants further investigation.

4. Effects of D-Allulose on Humans

4-1. Effect on postprandial glucose levels in healthy and prediabetic individuals

Human studies have shown 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 (prediabetes), consuming 5 g of D-allulose during 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 results highlight D-allulose as a potential dietary intervention to improve glucose control.

4-2. Effects in patients with type 2 diabetes: A new dietary approach

To assess its clinical utility, we investigated whether D-allulose could be integrated into the dietary therapy of diabetes.

(14.)

In our study, we compared a traditional diabetic diet – where calorie intake was calculated based on body weight and physical activity – with a modified diet containing 8.5 g of D-allulose per meal, maintaining the same macronutrient and calorie composition.

A diet enriched with D-allulose showed excellent postprandial glucose suppression in patients with type 2 diabetes (Figure 1).

This study, the first to use continuous glucose monitoring (CGM) to evaluate the use of D-allulose in dietary therapy, supports its potential as an innovative nutritional strategy in the management of diabetes.

Figure 1. Effect of a diabetic therapeutic diet containing D-allulose on postprandial blood glucose suppression

This figure shows the changes in blood sugar levels in patients with type 2 diabetes after consuming a conventional diabetic diet (dashed line) and a diabetic diet containing D-allulose (solid line).

A diet containing D-allulose significantly reduced postprandial blood glucose spikes after breakfast, lunch, and dinner.

4-3. The global burden of diabetes and the opportunities for 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 incidence of diabetes is increasing, with Asia experiencing particularly rapid growth.

In Malaysia, for example, the incidence of diabetes is constantly increasing.

A significant challenge is Ramadan, when Muslim patients fast from dawn to sunset (approximately 13 hours).

This fasting period carries the risk of daytime hypoglycemia, while iftar, the post-sunset meal, often leads to excessive food intake and an increased risk of postprandial and nocturnal hyperglycemia.

To address this issue, we conducted a study in patients with type 2 diabetes during Ramadan to examine the effect of D-allulose on glycemic fluctuations using CGM. (15.)

The results showed a significant reduction in postprandial glucose peaks and incremental area under the glucose curve (iAUC) after iftar.

These results suggest that D-allulose may help improve glycemic control during Ramadan (Figure 2).

This research highlights the potential of D-allulose as a novel dietary intervention in the management of diabetes, particularly in culturally specific settings where fasting-induced glycemic fluctuations pose a significant health risk.

Figure 2. Postprandial blood glucose-lowering effect of D-allose after iftar

(a) D-allose reduced the postprandial peak blood glucose level after iftar.

(b) The increase in the area under the curve (iAUC) of blood glucose elevation was significantly reduced.

5. Future directions and challenges

D-allulose represents a promising dietary strategy in the treatment of diabetes and obesity, as it can reduce postprandial glucose levels, enhance GLP-1 secretion, and promote fat burning.

As a naturally occurring, low-calorie sugar that offers 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 key to advancing medical applications and integrating D-allulose into evidence-based dietary strategies for the treatment of diabetes and obesity.

References

1. Imamura F, O'Connor L, Ye Z, Mursu J, Hayashino Y, Bhupathiraju SN, et al. Consumption of sugar-sweetened beverages, artificially sweetened drinks and fruit juices and the incidence of type 2 diabetes: a systematic review, meta-analysis and estimation of the 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 considerations: 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 maximum ineffective level of D-psicose in 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 the 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. A rare sugar syrup containing d-allulose but not high fructose corn syrup maintains glucose tolerance and insulin sensitivity in Wistar rats partly through 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. The rare sugar D-psicose prevents the progression and development of diabetes in a 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 humans: A systematic review and meta-analysis. PLoS One. 2023 Apr;18(4):e0281150.

11. Buranapin S, Kosachunhanan N, Waisayanand N, Yokoi H, Tokuda M. Effects of D-allulose co-administration with sucrose beverage on glucose tolerance and insulin levels in healthy Thai 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. Effect of D-allulose on glucose tolerance and insulin response to a standard oral sucrose load: results of a prospective, randomized, 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-lowering effect of D-psicose in borderline diabetes and the safety of long-term intake in healthy subjects. 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 on the efficacy of a diabetic diet containing the rare sugar D-allulose in patients with type 2 diabetes: a prospective, randomized, single-blind, 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.