Rare sugars curb appetite and mimic diabetes drugs in mice

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Apr 1 2025

Can rare sugars help control appetite and fight obesity? New research in mice suggests sweet solutions may lie in your gut hormones.

Study: Abilities of Rare Sugar Members to Release Glucagon-like Peptide-1 and Suppress Food Intake in Mice. Image Credit: Love Employee / Shutterstock

In a recent study published in the journal Nutrients, researchers in Japan evaluated the efficacy of rare sugars, specifically two aldohexoses and four ketohexoses (three rare sugars plus the common sugar D-fructose), in promoting glucagon-like peptide-1 (GLP-1) and reducing food intake in male murine (mice) models.

Study findings revealed that three rare sugar ketohexoses (D-allulose, D-tagatose, and D-sorbose), along with the common sugar D-fructose, significantly increased intestinal secretions of GLP-1 hormones and suppressed food intake in male mice, suggesting their potential as next-generation interventions for type 2 diabetes (T2D), obesity, and other metabolic diseases.

Background

Rare sugars are a category of sugars (monosaccharides) that exist in extremely low quantities in nature. Despite the term referring to more than 50 different kinds of sugars, these rare sugars collectively comprise less than 0.1% of naturally occurring sugars.

Rare sugars are known to taste sweet but are poorly metabolized in humans and other mammals, resulting in low calorie intake. Hence, they are hypothesized to constitute effective substitutes for common sugars (D-glucose and D-fructose) in combating the global pandemic of overweight, obesity, and associated metabolic disorders. Consequently, the large-scale industrial synthesis of some rare sugars has substantially ramped up in recent years.

Unfortunately, the mechanism underlying the biological effects of rare sugars and their derivatives remains largely understudied. Recent research by the present study group revealed the ability of D-allulose, a rare ketohexose, to promote the synthesis and release of intestinal glucagon-like peptide-1 (GLP-1) hormones, an effective means of suppressing food intake and alleviating hyperphagic obesity. Parallel investigations by other research groups suggest similar effects from rare aldohexoses and ketohexoses, but these effects have never been validated in vivo.

"…a chemical method, alkaline isomerization, has been established to produce multiple rare sugars from isomerized sugar. This process yields rare sugar syrup containing at least 13% rare sugars and is more cost-effective than enzymatic synthesis. The rare sugar syrup is a mixed syrup containing 45% D-glucose, 29% D-fructose, 5% D-allulose, 5% D-sorbose, 2% D-tagatose, 1% D-allose, and 13% other sugars, among which D-allulose, D-sorbose, D-tagatose, and D-allose are classified as rare sugars."

About the study

The present study aims to shed light on the in vivo efficacies of several rare sugars in promoting anti-metabolic disease outcomes, particularly increased GLP-1 secretions and suppression of food intake. Since the current industrial gold standard of rare sugar use revolves around the manufacture of rare sugar syrup, the present study focuses on the sugars that make up the syrup, namely two aldohexoses (D-glucose, D-allose) and four ketohexoses (D-fructose, D-allulose, D-tagatose, D-sorbose).

In vivo experiments were conducted on male C57BL/6J mice (8–20 weeks old), divided into cohorts corresponding to two separate dosages (1 g/10 mL/kg or 3 g/10 mL/kg) of individual sugar solutions or an equivalent saline solution (control). Experimental procedures comprised overnight fasting followed by the corresponding treatment's peroral (po) administration (sugar or saline solution).

GLP-1 levels were specifically measured in portal vein plasma 1 hour post-administration, a method chosen to optimize detection of intestinal hormone secretion. Blood samples were collected under anesthesia and analyzed using active GLP-1 ELISA kits.

Food consumption after solution administration was measured using cumulative energy intake as a proxy, where the quantity of food eaten was weighed at 1, 3, 6, and 24 hours following solution administration.

Finally, statistical comparisons between the different treatment regimes were performed using one-way analysis of variance (ANOVA), the Kruskal–Wallis test, and the Mann–Whitney test, as implemented in the Prism 10 software platform.

Study findings

Active GLP-1 evaluations revealed that ketohexoses (D-fructose, D-allulose, D-tagatose, D-sorbose) but not aldohexoses (D-glucose, D-allose) elevated plasma GLP-1 levels between 3–4-fold (1 g/10 mL/kg compared with saline controls). Notably, these elevations were dose-dependent and increased to 4–6-fold in the 3 g/10 mL/kg cohort. The GLP-1-stimulating efficacy among the four ketohexoses was statistically indistinguishable.

D-allose at higher doses showed a non-significant trend toward increased GLP-1 levels, suggesting a possible minor role.

Food intake tests revealed that all evaluated sugars, except D-glucose, promoted short-term (~6 hours) suppression of food intake. Surprisingly, the aldohexose D-allose suppressed food intake (3 g/10 mL/kg) despite not impacting GLP-1 secretions. These findings were also dose-dependent, with 3 g/10 mL/kg demonstrating more potent food suppression than 1 g/10 mL/kg. This suppression effect was no longer observed at 24 hours. The food intake-suppressing efficacy of the four ketohexoses was also statistically indistinguishable.

Given D-allose's surprising GLP-1-independent effects on food intake suppression, researchers conducted GLP-1 antagonism experiments using the antagonist Ex(9-39) at 600 nmol/kg. This experiment confirmed that D-allose achieves food intake suppression via a non-GLP-1-dependent mechanism, as demonstrated by a blunt response to ketohexoses (no food intake suppression compared with saline) but an unhindered food intake suppression response for D-allose.

Conclusions

The present study highlights the ability of rare sugar syrup components, specifically ketohexoses (D-fructose, D-allulose, D-tagatose, D-sorbose), to promote intestinal GLP-1 secretion in male murine models in a dose-dependent pattern. These ketohexoses and D-allose (an aldohexose) were also found to significantly reduce food intake dose-dependently for ~6 hours following po administration.

Together, these findings scientifically validate the benefits of rare sugars and rare sugar syrup as natural functional foods that can promote glycemic control and prevent overeating, the first step in addressing today's global obesity and metabolic disease pandemics. While not explicitly tested in this study, these findings raise the possibility that future human studies could explore their long-term efficacy and safety.