Discussion
Significant reductions in the consumption of added sugars, as recommended by current guidelines,10–13 may necessitate the use of sugar substitutes to enhance food sweetness and palatability. Reduced calorie sweeteners currently approved by the FDA include sugar alcohols (polyols) such as erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol and hydrogenated starch hydrolysates. Studies of subjects with and without DM have shown that sugar alcohols produce a lower postprandial glucose response than sucrose or glucose and have lower available energy.14 15 Sugar alcohols contain, on average, about 2 calories/g (one-half the calories of other sweeteners such as sucrose). Use of sugar alcohols as sweeteners reduces the risk of dental caries. However, there is no evidence that the amounts of sugar alcohols likely to be consumed will reduce glycemia, energy intake or body weight. The use of sugar alcohols appears to be safe; however, they may cause diarrhea. The FDA has approved six non-nutritive sweeteners for use in the USA. These are acesulfame potassium, aspartame, neotame, saccharin, stevia and sucralose. Clinical studies involving subjects without diabetes provide no indication that non-nutritive sweeteners in foods will cause weight loss or weight gain.14 15
Rare sugar D-allulose as a substitute sweetener is produced through the isomerization of D-fructose by D-tagatose 3-epimerases or D-allulose 3-epimerases. It is a low energy monosaccharide sugar naturally existing in very small quantities in some fruits, including kiwis (9.4 mg/100 g food), figs (29.6 mg/100 g food) and raisins (38.7 mg/100 g food).15 D-allulose has approximately 70% relative sweetness to sucrose with 0.2 kcal/g that is a 95% calorie reduction compared with sucrose.16 With the advent of technology that allows the production of D-allulose enzymatically on a large scale,28 29 it is now possible to conduct studies of utility of D-allulose in food and beverages. D-Allulose possesses high value as a food ingredient and dietary supplement, and may carry a variety of physiological functions, such as improving insulin resistance, antioxidant enhancement, reducing endoplasmic reticulum stress and hyperglycemic control, which makes it a very attractive option. However, so far, glucose suppressive effects of D-allulose have been mostly shown in animal studies and small clinical studies performed in Asian populations,17–20 and only limited data exist in Westerners.21 22
Our study was the largest to test the effects of D-allulose in Westerners, including white and African-American, and results can be summarized as follows: (1) D-allulose administered in addition to a standard sucrose load led to a dose-dependent reduction of plasma glucose at 30 min compared with placebo; (2) although plasma glucose was not reduced at the other time points and AUC was similar between D-allulose and placebo, there was a dose-dependent reduction in plasma glucose excursion compared with placebo; (3) the effects of D-allulose on insulin levels and insulin excursion were similar to those on plasma glucose; (4) D-allulose effects appeared to be consistent in both white and African-American subjects; (5) the administration of escalating doses of D-allulose appeared to be safe.
Various physiological activities of D-allulose have been reported so far. Of those, its postprandial glucose suppressive effect has been proven by both animal and clinical studies.17–20 Several animal experiments have reported antiobesity and antidiabetic effects of D-allulose.23–27 There are multiple potential mechanisms that contribute to the antiglycemic effect of D-allulose. In one study, the antiglycemic effect of D-allulose was attributed to its ability to increase glucagon-like peptide 1 levels.30 Shintani et al attributed the improved glucose tolerance and insulin sensitivity in Wistar rats to changes in hepatic glucokinase.31 Another study in animals suggested that the postprandial glucose suppression could be at least partly related to the inhibition of intestinal α-glycosidase.17 In this latter study, D-allulose was also shown to suppress hepatic lipogenic enzyme activity and reduce intra-abdominal fat accumulation. Overall, it appears that the effect of D-allulose is independent of insulin and the changes in insulin concentrations during these experiments are secondary to changes in plasma glucose.
In small clinical trials conducted in Japan, D-allulose significantly suppressed blood glucose elevation after glucose loading study on healthy adults.19 20 These studies also suggested that supplemental D-allulose in the diet could reduce postprandial glycemic response and might have antidiabetic effects. In addition, studies on rats and humans did not detect any increase in carbohydrate energy expenditure by D-allulose absorbed through the small intestine, even at the upper limit of concentration.17–20 Finally, clinical studies have also shown that D-allulose does not affect blood glucose or insulin levels after ingestion,19 and in a randomized, double-blind, controlled trial of long-term ingestion of D-allulose 3 times a day with meal for 12 weeks in healthy human subjects did not show any abnormal effects or clinical problems.20
Early clinical trials of D-allulose demonstrating its antidiabetic and antiobesity effects have been carried out in Kagawa (Japan). In 2011, a rare sugar syrup (RSS), which contains 76% of regular syrup (D-glucose and D-fructose), 6% of D-allulose and 18% of other saccharides including D-allose and D-sorbose, has been developed and commercialized in Japan and D-allulose and D-allulose-containing RSS have already been used for various foods.32 Two small studies conducted in subjects with or without DM in Canada showed none or modest reductions in the postprandial blood glucose response to oral glucose with administration of D-allulose.21 22 Our investigation is the largest conducted so far in Westerners, including both white and African-American, and using multiple D-allulose dosing regimens. The results of our investigation, which confirms D-allulose properties in reducing postprandial glycemic response, as well as safety, among Westerners, can set the basis for the potential use of D-allulose in a population where reduction of added sugar is of paramount importance. The results of the present study, along with the results in previously published studies, suggest that adding 5–10 g of D-allulose to 50 g of sugar is sufficient to reduce the postprandial glycemia attributed to sugar. This ratio of D-allulose-to-sugar content is consistent with the composition of the currently marketed RSS, which contains only 6% of D-allulose and is well tolerated. Thus, the amount of D-allulose that would be necessary for an effect and that is reasonable in food products is 5%–10% of added table sugar.
It is noteworthy that targeting postprandial blood glucose spike may have beneficial clinical effects independent of the average blood glucose levels as estimated by HbA1c measurements.33 34 In endothelial cell cultures there is rapid adaptive downregulation of oxidative burst induced by high concentrations of dextrose suggesting that repeated spikes of blood glucose levels are more likely to cause oxidative damage than sustained levels of blood glucose.35 Future studies should explore more in depth the underlying mechanisms by which D-allulose reduces glucose and insulin levels as well as its long-term effects, including its potential to impact clinically meaningful outcomes.
Study limitations
Our study was of short duration and used a single administration of D-allulose in any given day of testing, therefore the effects and safety of long-term administration were not assessed and would require dedicated studies. It is in fact pivotal to identify the potential negative effects of administered rare sugars. For example, trehalose, a rare disaccharide, was found to enhance Clostridium difficile disease.36 We did not study the effects of doses of D-allulose higher than 10 g. Although our dosing is in line with previously reported studies in Asians, we cannot rule out the possibility that higher doses would be more effective and well tolerated in Western populations. Our study was not powered to detect differences in treatment according to race, and included a limited number of African-American subjects. Therefore, our results showing consistent treatment effects in white and African-American subjects should be interpreted with caution and considered as hypothesis generating.