Allulose – New Sweetener on the Block

SPONSORED CONTENT: With low carb and ketogenic diets having exploded in popularity, there’s growing interest in identifying or synthesizing new sweetening agents to allow people to enjoy occasional treats without wreaking havoc on their blood sugar and insulin. Several such substances are already in widespread use, but most have drawbacks. So the search is constantly on to find new sweeteners that have only benefits and no drawbacks—or, at the very least, ones for which the pros vastly outweigh any potential cons. Enter allulose.

What is Allulose?

Allulose is a monosaccharide epimer of fructose, formally called D-psicose. It’s found naturally in jackfruit, figs, raisins, and maple syrup. Humans lack the enzymes to digest allulose, so it is largely excreted, but without the unpleasant GI effects induced by certain sugar alcohols. (It’s excreted primarily in the urine and has very low colonic microbial fermentability.) It’s an ideal sweetener for those on ketogenic or reduced carb diets, as it has no impact on blood glucose or insulin levels when consumed in reasonable amounts. Ketogenic and low-carb diets are used for a host of reasons other than weight loss, but for those who are looking to lose body fat, allulose may be an ideal sweetener since it is nearly calorie-free and has been shown to have a small but notable impact on reducing body fat mass.

Metabolic Effects of Allulose

Scientific evidence supports the low fermentability and negligible metabolism of allulose in humans. In healthy subjects, allulose was shown to be absorbed in the small intestine but not metabolized. In one study, approximately 90% of ingested allulose was recovered in urine, with 1.79-5.65% recovered in feces.

Allulose has interesting properties beyond these attributes, such as improving glucose tolerance and insulin sensitivity, and reducing adipocyte inflammation. Co-ingestion of allulose in a mixed (carbohydrate-containing) meal has been shown to modulate the postprandial glycemic impact of the meal. This has been demonstrated in healthy subjects as well as those with pre-diabetes. In one study, administration of 5g allulose in tea consumed with a mixed meal (425 calories, 84.5g carbohydrate, 13.3g protein, 3.7g fat) resulted in significant decreases in postprandial glucose and glucose area under the curve compared to the control tea (containing 10mg aspartame). The same study assessed longer term safety of allulose, wherein subjects consumed 5g with meals three times daily for 12 weeks. At the end of 12 weeks and after 4 weeks of follow-up after the intervention, no abnormal effects or clinical problems were observed.

Similar findings were seen in a study of healthy young subjects given various doses of allulose along with 75g of maltodextrin as a beverage. Compared to taking the maltodextrin alone, the elevations in blood glucose and insulin were suppressed with co-ingestion of 5g or 7.5g of allulose, but not with 2.5g. Suppression of insulin is noteworthy, because owing to the prevalence of metabolic syndrome and other hyperinsulinemic conditions, a reduction in glucose levels at the expense of substantially elevated insulin would be undesirable.

The precise mechanisms by which allulose reduces postprandial glucose excursions is not known for certain, but researchers believe it may be due to inhibition of alpha-glucosidase, an intestinal brush border enzyme that breaks down starch and disaccharides into glucose. Another hypothesis is that allulose may promote hepatic uptake of glucose and accumulation of glycogen, increasing glucose tolerance.

Animal studies provide evidence that allulose has other potentially beneficial effects, such as suppressed activity of hepatic lipogenic enzymes, resulting in reduced abdominal adipose deposition and triglyceride accumulation in the liver. Rat studies showing that allulose has an energy deposition efficiency of 0.3% that of sucrose led researchers to write that the energy value of this compound is effectively zero, and that allulose “is a rare sugar providing zero energy that may be useful in sweeteners for obese people as an aid for weight reduction.”

Preliminary evidence in humans suggests allulose may have a small beneficial impact on reducing body weight, total fat mass, and abdominal fat mass. A study of Korean adults showed that compared to placebo (sucralose), allulose taken at 4g or 7g per day for 12 weeks resulted in significant reductions in body fat mass, with the 7g dose also resulting in reduced abdominal fat as measured by CT scan.

Confusing Label

Because it is technically a sugar (it even bears the suffix “-ose”), the FDA currently requires that allulose be listed as sugar in the Nutrition Facts panel on food labels, along with its full amount of carbohydrate and calories. This is misleading, however, because owing to allulose not being metabolized by the body, it has just 1/10th the calories of sucrose—only 0.4 calories/gram. Patients should be made aware of this, so they will understand how to properly read labels of products containing allulose.

Over time, we will likely see more products entering the market being made with allulose. Mark Sisson, author of The Primal Blueprint and creator of the wildly popular site, Mark’s Daily Apple, posted a nice overview of allulose and the related science.

We received a lot of email on the Designs For Health sponsored blog on Allulose – being a not widely available sweetener, there was much curiosity from readers- particularly given its reported favorable gut and metabolic profiles. That said, my IFM colleague and friend Dr. Robert Hedaya, emailed us with a handful of concerns on the research cited in the blog. Designs for Health responded to Dr. Hedaya’s questions. We’re reprinting their exchange for you here. Note references cited at the end of the exchange.

I read with interest the Allulose story, then I looked at the references via Sisson’s website. The data used to support these claims (I know they are framed as preliminary, but people are going to jump on this ‘new’ sweetener) is really so sparse—about 25 rats.

Thank you Dr. Hedaya for your questions.

Although this is a burgeoning area of research and clinical investigation, the references cited here contain both human studies as well as mouse models. In total, the human subjects of the collective literature cited here equals over 180 subjects. While some may view this as a relatively small “n” for scientific evidence, it is encouraging to see that human clinical trials, and not purely preclinical, cell cultures and rat studies, have been performed.  

With respect to your observations surrounding the other referenced literature and their “n” – please see below:

The authors assessed the availability of d-psicose [allulose] absorbed in the small intestine by measuring carbohydrate energy expenditure (CEE) by indirect calorimetry. They measured the urinary excretion rate by quantifying d-psicose in urine for 48 hours. To examine d-psicose fermentation in the large intestine, the authors measured breath hydrogen gas and fermentability using 35 strains of intestinal bacteria. Six healthy subjects participated in the CEE test, and 14 participated in breath hydrogen gas and urine tests. d-Psicose fermentation subsequent to an 8-week adaptation period was also assessed by measuring hydrogen gas in 8 subjects.1

Eight healthy male subjects were housed within a metabolic ward for 1 week. The orally administered 776 nCi [14C(U)]-rare sugar (99% purity), in a beverage containing 15g of unlabeled sweetener was consumed following a light breakfast. Blood, urine, fecal and expired air samples were collected at baseline and at various time points through 168 hr for detection of the radiotracer and potential metabolites. Overall, TRA 14C recovery was approximately 90%. High performance liquid chromatographic fractions analyzed with AMS showed the majority of the radiotracer was intact (TRA 80.3% plasma; 83.6% urine; 16% fecal). The 14C-rare sugar was the most abundant compound in the plasma and excreta, demonstrating that this novel sugar is absorbed, but not metabolized. 2

Clinical study was conducted to investigate the safety and effect of D-psicose on postprandial blood glucose levels in adult men and women, including borderline diabetes patients. A randomized double-blind placebo-controlled crossover experiment of single ingestion was conducted on 26 subjects who consumed zero or 5 g of D-psicose in tea with a standard meal. The blood glucose levels at fasting and 30, 60, 90, and 120 min after the meal were compared. The blood glucose level was significantly lower 30 and 60 min after the meal with D-psicose (p<0.01, p<0.05), and a significant decrease was also shown in the area under the curve (p<0.01). The results suggest that D-psicose had an effect to suppress the postprandial blood glucose elevation mainly in borderline diabetes cases. A randomized double-blind placebo-controlled parallel-group experiment of long-term ingestion was conducted on 17 normal subjects who took 5 g of D-psicose or D-glucose with meals three times a day for 12 continuous weeks. Neither any abnormal effects nor clinical problems caused by the continuous ingestion of D-psicose were found.3

An examination was conducted to verify D-psicose suppressed the elevation of blood glucose and insulin concentration in a dose-dependent manner under the concurrent administration of maltodextrin and D-psicose to healthy humans. Twenty subjects aged 20-39 y, 11 males and 9 females were recruited. A load test of oral maltodextrin was conducted as a randomized single blind study. The subjects took one of five test beverages (7.5 g D-psicose alone, 75 g maltodextrin alone, 75 g maltodextrin +2.5, 5 or 7.5 g D-psicose). Blood was collected before an intake and at 30, 60, 90 and 120 min after an intake. Intervals of administration were at least 1 wk. The load test with 75 g maltodextrin showed significant suppressions of the elevation of blood glucose and insulin concentration under the doses of 5 g or more D-psicose with dose dependency. An independent administration of 7.5 g D-psicose had no influence on blood glucose or insulin concentration. D-Psicose is considered efficacious in the suppression of the elevation of blood glucose concentration after eating in humans.4

A preliminary study with 121 Korean subjects (aged 20–40 years, body mass index ≥ 23 kg/m2). A randomized controlled trial involving placebo control (sucralose, 0.012 g × 2 times/day), low d-allulose (d-allulose, 4 g × 2 times/day), and high d-allulose (d-allulose, 7 g × 2 times/day) groups was designed. Parameters for body composition, nutrient intake, computed tomography (CT) scan, and plasma lipid profiles were assessed. Body fat percentage and body fat mass were significantly decreased following d-allulose supplementation. The high d-allulose group revealed a significant decrease in not only body mass index (BMI), but also total abdominal and subcutaneous fat areas measured by CT scans compared to the placebo group. There were no significant differences in nutrient intake, plasma lipid profiles, markers of liver and kidney function, and major inflammation markers among groups. These results provide useful information on the dose-dependent effect of d-allulose for overweight/obese adult humans. Based on these results, the efficacy of d-allulose for body fat reduction needs to be validated using dual energy X-ray absorption.5

Also I wonder who is funding these studies-there is a lot of money to be made of a literature can establish the existence and validity of a safe, not to mention even healthy sugar.

We appreciate and concur with your concern around the financial underpinnings of research. While difficult to determine the precise funding sources, the published literature referenced in this blog article notes “None of the authors had any personal or financial conflicts of interest.”

Additionally, I am highly suspicious of these studies because the cephalic phase of insulin release (not to mention cephalic insulin resistance) is not addressed.

With respect to cephalic phase of insulin release, this would be a fascinating area for research around allulose/D-psicose, particularly since D-psicose showed significant suppressions of the elevation of blood glucose and insulin concentration in the above mentioned study involving oral maltodextrin tolerance test.4 There does seem to be some ambiguity; however, as to the existence of a cephalic secretory phase for insulin – with some studies supporting its occurrence, while others do not.6 In terms of cephalic insulin resistance, some evidence indicates no clear differences in responses between individuals without a known family history of Type 2 diabetes or with impaired fasting (IFG) or impaired glucose tolerance (IGT). In research with individuals who had first-degree relatives with a history of DM2, Eliasson, et al. did not see any relation between the cephalic phase of insulin release and subsequent post-prandial insulin secretion.7 This is clearly an area for additional investigation.  

Finally, rats are not humans. Given all this, and the many disappointments medicine delivers to the public (BCP’s, the food pyramid, etc) it is important that we should be flashing a yellow ‘caution’ signal to the functional medicine community, advocating for more research before we support the use of this in foods.

Agreed Dr. Hedaya – there is a clear distinction between rat and human physiology and we certainly don’t want to conflate the two or extrapolate excessively; however, as noted above, the majority of the studies cited in this piece were of human trials. In addition, rat studies serve as an important aspect of clinical research to help identify potential mechanisms and generate hypotheses that can be further explored in the context of human subjects.  

References

1. Iida T, Hayashi N, Yamada T, Yoshikawa Y, Miyazato S, Kishimoto Y, Okuma K, Tokuda M, Izumori K. Failure of d-psicose absorbed in the small intestine to metabolize into energy and its low large intestinal fermentability in humans. Metabolism. 2010 Feb;59(2):206-14. doi: 10.1016/j.metabol.2009.07.018.
2. Williamson, P., et al. (2014). “A single-dose, microtracer study to determine the mass balance of orally administered, 14C-labeled sweetener in healthy adult men (LB450).”  28(1_supplement): LB450.
3. Hayashi N, Iida T, Yamada T, Okuma K, Takehara I, Yamamoto T, Yamada K, Tokuda M. Study on the postprandial blood glucose suppression effect of D-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjects. Biosci Biotechnol Biochem. 2010; 74(3):510-9.
4. Iida T, Kishimoto Y, Yoshikawa Y, Hayashi N, Okuma K, Tohi M, Yagi K, Matsuo T, Izumori K. Acute D-psicose administration decreases the glycemic responses to an oral maltodextrin tolerance test in normal adults. J Nutr Sci Vitaminol (Tokyo). 2008 Dec;54(6):511-4.
5. Han, Y., Kwon, E. Y., Yu, M. K., Lee, S. J., Kim, H. J., Kim, S. B., Kim, Y. H., … Choi, M. S. (2018). A Preliminary Study for Evaluating the Dose-Dependent Effect of d-Allulose for Fat Mass Reduction in Adult Humans: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients, 10(2), 160. doi:10.3390/nu10020160
6. Eliasson, B., Rawshani, A., Axelsen, M., Hammarstedt, A., & Smith, U. (2017). Cephalic phase of insulin secretion in response to a meal is unrelated to family history of type 2 diabetes. PloS one, 12(3).
7. Veedfald S, Plamboeck A, Deacon CF, Hartmann B, Knop FK, Vilsbøll T, Holst JJ. Cephalic phase secretion of insulin and other enteropancreatic hormones in humans. Am J Physiol Gastrointest Liver Physiol. 2016 Jan 1;310(1):G43-51.