Abilities of Rare Sugar Members to Release Glucagon-like Peptide-1 and Suppress Food Intake in Mice

Abstract

Background/Objectives: Rare sugars, which naturally exist in small quantities, have gained attention as next-generation functional sugars due to their sweetness and low calorie content. Some of them have already been commercialized. Rare sugar-containing syrups, produced through alkaline isomerization of high-fructose corn syrup, are effective in preventing obesity and type 2 diabetes. However, the mechanisms underlying these effects remain incompletely understood. Recently, D-allulose has been found to improve hyperphagic obesity by stimulating the secretion of the intestinal hormone glucagon-like peptide-1 (GLP-1). The present study aimed to determine the comparative effects of aldohexoses (D-glucose, D-allose) and ketohexoses (D-fructose, D-allulose, D-tagatose, D-sorbose) on GLP-1 secretion and food intake in male mice. Method and Results: Single peroral administration of four ketohexoses at 1 and 3 g/kg, but not aldohexoses at 1 and 3 g/kg, significantly increased plasma GLP-1 concentrations with comparable efficacy. Moreover, these ketohexoses at 1 g/kg suppressed food intake in the short term, an effect blunted by GLP-1 receptor antagonism. In contrast, zero-calorie D-allose at 3 g/kg suppressed feeding without raising plasma GLP-1 levels. Conclusions: These results demonstrate that D-allulose, D-tagatose, and D-sorbose, which are low-calorie rare sugars classified as ketohexoses, suppress food intake through promoting GLP-1 secretion, showing their potential to prevent and/or ameliorate type 2 diabetes, obesity and related diseases.

Keywords: GLP-1; allose; allulose; food intake; fructose; rare sugars; sorbose; tagatose.

Figure 1

Chemical structures of the monosaccharides/hexoses investigated in this study: four rare sugars and two nonrare sugars. D-glucose and D-allose are aldohexoses that contain an aldehyde group (A). D-fructose, D-allulose, D-tagatose, and D-sorbose are ketohexoses that contain a ketone group (B). Of these, D-allose, D-allulose, D-tagatose, and D-sorbose are rare sugars, indicated by an asterisk (*).

Figure 2

Comparison of plasma active GLP-1 concentrations after administration of six monosaccharides: All ketohexoses, except aldohexoses, promote GLP-1 secretion. Overnight-fasted C57BL/6J mice received monosaccharide solutions at either 1 g/kg (A) or 3 g/kg (B) via a stainless-steel feeding needle directly into the stomach. Blood samples were collected from the portal vein 1 h after administration, and plasma active GLP-1 concentrations were measured. The dashed lines in (A,B) represent the mean value of the saline group. n = 5–15. Different letters indicate significant differences with p < 0.05 determined by one-way ANOVA followed by Tukey’s test. GLP-1: glucagon-like peptide-1. Sal: saline. Glu: D-glucose. Allo: D-allose. Fru: D-fructose. Allu: D-allulose. Tag: D-tagatose. Sor: D-sorbose.

Figure 3

Single peroral administration of rare sugars or ketohexoses suppresses food intake. Mice were fasted overnight (16 h) and then perorally administered either saline or a monosaccharide solution ((A) D-glucose, (B) D-allose, (C) D-fructose, (D) D-allulose, (E) D-tagatose, (F) D-sorbose) at doses of 1 g/kg or 3 g/kg. The mice were fed immediately after administration, and cumulative food intake was measured at 1 h, 3 h, and 6 h after administration. The energy values of the administered solutions are indicated at 0 h in each figure; cumulative food intake includes the energy from the administered monosaccharides. n = 7–16. † p < 0.05, †† p < 0.01 by one-way ANOVA followed by Dunnett’s test compared to the saline po group. * p < 0.05, ** p < 0.01 by one-way ANOVA followed by Tukey’s test for comparisons between 1 g/kg and 3 g/kg.

Figure 4

Comparison of the anorexigenic effects of monosaccharides. The data on cumulative food intake after administration of the six monosaccharides shown in Figure 3 were reanalyzed as relative cumulative food intake at 1 h (A), 3 h (B), or 6 h (C) after injection. The saline group was included in all experiments conducted on different days. Therefore, the cumulative food intake after monosaccharide administration was normalized to the saline group results from the same day. The dashed lines in each figure indicate the average value of the saline group. n = 104 for the saline group and n = 7–11 for other groups. † p < 0.05, †† p < 0.01 by the Kruskal–Wallis test followed by Dunn’s test vs. the saline group. * p < 0.05, ** p < 0.01 by the Mann–Whitney test. Sal: saline, Glu: D-glucose. Allo: D-allose. Fru: D-fructose. Allu: D-allulose. Tag: D-tagatose. Sor: D-sorbose.

Figure 5

Pretreatment with GLP-1 receptor antagonist exendin(9–39) blunts the anorexigenic effects of ketohexose administration but not those of D-allose. (A–C) Exendin(9–39) at 600 nmol/kg was administered intraperitoneally to overnight-fasted mice 15 min before administration of either saline or monosaccharides (3 g/kg: D-allose; 1 g/kg: D-fructose, D-allulose, D-tagatose, and D-sorbose). Cumulative food intake was measured at 1 h (A), 3 h (B), and 6 h (C) after administration. These experiments were performed over multiple days; therefore, the results are presented as relative cumulative food intake (% kcal relative to the saline group). (D–F) To compare the effects of exendin(9–39), the results from Figure 5A–C and Figure 4 were reanalyzed for each time point. † p < 0.05, †† p < 0.01 by Kruskal–Wallis test followed by Dunn’s test vs. saline group. * p < 0.05, ** p < 0.01, and p = 0.068 by Mann–Whitney test between the two groups. Sal: saline, Glu: D-glucose. Allo: D-allose. Fru: D-fructose. Allu: D-allulose. Tag: D-tagatose. Sor: D-sorbose.