Vol.1, No.2, 66- 71 (2011)
doi:10.4236/ojpm.2011.12010
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJPM/
Open Journal of Preventive Medicine
The effects of 90-day feeding of D-psicose syrup in male
Wistar rats
Tatsuhi ro M atsuo1*, Reika Ishii1, Yoko Shirai 2
1Faculty of Agriculture, Kagawa University, Kagawa, Japan; *Corresponding author:
2National Institute for Materials Science, Tsukuba, Japan.
Received 2 June 2011; revised 14 Ju ly 2011; accepted 30 July 2011.
AB S TRACT
D-Psicose i s a rar e sug ar present in smal l quan -
tities in natural products. In a previous study,
we showed that D-psicose suppresses increase
in plasma glucose and reduces body fat accu-
mulation in rats. Based on acute and chronic
toxicit y testing in rats, D-psicose is classified as
an ordinary and safe substance. Recently, we
developed a high D-psicose syrup (PS) made
from high fructose corn syrup (HFCS) by the
alkaline isomerization method. However, the
safety of PS as a food additive has not been
demonstrated . In this stud y, we inv estigated t he
effects of 90-day feeding of PS in male Wistar
rats. The rats were fed diets containing 3%
D-psicose (control) or 4.3% PS for 90 days. The
body weight gain and intra-abdominal adipose
tissue weight did not differ between the control
and PS group. The weights of the tissues did
not differ between the two dietary groups. In
clinical chemistry and hematological analyses,
no differences were found between the control
and PS groups. No gross pathological findings
were evident at dietary doses of 4.3% PS.
Therefore, the present study found no adverse
effects of PS in rats fed a diet containing 4.3%
PS for 90 days.
Keywords: D-Psicose; D-Psicose Syrup;
90-Day Feeding; Pathological Tests; Rat
1. INTRODUCTION
D-Psicose (D-ribo-2-hexulose), a C-3 epimer of D-
fructose, is a “rare sugar” present in small quantities in
commercial mixtures of D-glucose and D-fructose ob-
tained by hydrolysis of sucrose or isomerization of D-
glucose [1]. D-Psicose is also present in processed cane
and beet molasses [2], and is found in wheat [3], Itea
plants [4], and in the antibiotic psicofranine [5]. In the
2000s, D-psicose began to be made using an enzymatic
method on a large scale, making it possible to conduct
biochemical and nutritional studies [6]. Examining the
effects of D-psicose on glucose and lipid metabolism, we
found that D-psicose is a sweet monosaccharide that
provides no energy to growing rats and leads to less in-
tra-abdominal fat accumulation than D-glucose and D-
fructose in rats [7,8]. In addition, we suggested previ-
ously that supplemental D-psicose can lower plasma
glucose levels [9]. Toyoda et al. [10] suggested that D-
psicose can prevent postprandial hyperglycemia by im-
proving the translocation of glucokinase from the nu-
cleus to the cytoplasm in the liver of diabetic rats. D-
psicose is expected to have a beneficial effect in the con-
trol of blood glucose levels in type 2 diabetes.
Based on acute toxicity testing in rats, D-psicose is
classified as an ordinary substance, with an oral LD50
value of 16 g/kg in male Wistar rats [11]. D-psicose,
which is naturally present in foods such as fruit juice and
fruit cereal, is derived from D-fructose by the cooking
process [2,12]. Oshima et al. [13] reported that in high-
sugar food products, heat processing had a marked effect
on the production of D-psicose. In particular, con-fec-
tionery products and seasoning sauces exhibited higher
D-psicose content (0.005 - 1.3 mg/g) than other products
[13]. As a result, most people ingest a limited amount of
D-psicose on a daily basis. Furthermore, we examined
the effects of sub-chronic (90 days) and long-term feed-
ing (12 - 18 months) of D-psicose to rats prior to its
utilization as a physiologically functional food [14,15].
We showed that 3% D-psicose in the diet had no adverse
effects in rats.
Recently, we developed a new product, high D-psi-
cose syrup (85% D-psicose) made from high fructose
corn syrup (HFCS) by the alkaline isomerization method.
D-Psicose syrup (PS) can be easily and cost-effectively
produced compared to D-psicose. However, as PS in-
cludes small amounts of unknown ingredients (probably

T. Matsuo et al. / Open Journal of Preventive Medicine 1 (2011) 66-71
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJPM/
67 67
several monosaccharides), the safety of PS as a low-
energy sweetener or food additive is not clear.
In this study, to assess the safety of PS, the effects of
90-day feeding of PS was conducted in rats at a dietary
dose of 4.3% PS (including 3% D-psicose). The objective
of this study was to determine whether PS can be safety
used as a functional food similar to D-psicose.
2. MAT ERIALS AND MET HODS
All procedures involving animals were approved by
the Animal Care Committee of Kagawa University.
2.1. Ani m al s and Experimental Diets
Twenty male Wistar rats (3 weeks old) were obtained
from Japan SLC (Shizuoka, Japan). They were fed CE-2,
a commercial rodent diet (CLEA, Tokyo, Japan) and
water ad libitum until they were 4 weeks old . They were
caged individually at 22˚C ± 2˚C, with lights on from
08:00 to 20:00. The rats were randomly divided into two
groups of 10 (control and PS groups). We adopted D-
psicose as a control for PS because the safety of D-psi-
cose was confirmed by our previous studies in animals
and humans [11,14-16]. The compositions of experi-
mental diets are shown in Tab le 1. The compositions of
PS were as follows: D-psicose, 70%; water, 17%; un-
known ingredients, 13%. The control and PS diets in-
cluded 3% D-psicose in CE-2, a commercial rodent chow
(CLEA). The amount of test carbohydrates was deter-
mined with reference to previous studies concerning
D-psicose [13] or sucralose, the LD50 of which is the
same as that of D-psicose [17,18]. Each group of rats
was given free access to food and water for 90 days. PS,
which was made from HFCS by the alkaline isomeriza-
tion method, and D-psicose, which was made enzymati-
cally from D-fructose, were gifts from Rare Sugar
Production Technical Research Laboratories, LLC (Ka-
gawa, Japan). The HFCS used as a raw material for PS
was supplied by Matsutani Chemical Industry, Co., Ltd.
(Hyogo, Japan).
Table 1. Composition of experimental diets.
Groups Control D-Psicose syrup
Ingredients g/kg
CE-2 95.7 95.7
D-Psicose syrup* 0.0 4.3
D-Psicose 3.0 0.0
Sucrose 0.5 0.0
Distilled water 0.7 0.0
Total 1000.0 1000.0
*17% of water is included. D-Psicose includs 85% of solid content.
2.2. Experimental Design
After 90 days of feeding, rats in each group were
fasted for 4.5 h beginning at 06:00, and then anesthe-
tized by intraperitoneal administration of sodium pento-
barbital. Blood was collected from the abdominal aorta
for clinical hematological analysis and to obtain serum
for chemical analysis. The rats were exsanguinated. The
brain, heart, lungs, liver, pancreas, kidneys, adrenal
glands, spleen, testes, intra-abdominal adipose tissues
(epididymal, perirenal, and mesenteric), and muscle tis-
sues ( sole us, gastr o cne mi us, a nd plantarius) were rapidly
removed and weighed. Parts of the liver, kidneys, and
small intestine (about 5 mm of the end of the jejunum)
were preserved in 10% neutral buffered formalin for
histopathological examinations. The stomach, small in-
testine, large intestine, and cecum were also rapidly re-
moved and weighed. In addition, the small and large
intestine length, surface area, and cecal content weight
were measured.
2.3. A nalysis
The following hematological and clinical chemistry
parameters were evaluated white blood cell count
(WBC), red blood cell count (RBC), hemoglobin (Hb),
hematocrit (Ht), mean corpuscular volume (MCV), mean
corpuscular hemoglobin (MCH), mean corpuscular he-
moglobin concentration (MCHC), platelet count (PLT),
total protein (TP), ratio of albumin and globulin (A/G),
albumin (ALBU), globulin (GLO), aspartate amino-
transferase (AST), alanine aminotransferase (ALT), uric
acid (UA), urea nitrogen (BUN), creatinine (CREA),
calcium (Ca), iron (Fe), total cholesterol (CHO), triglyc-
eride (TG), glucose (GLU), and free fatty acids (FFA).
The hematological and chemical analyses were per-
formed by Shikokuchuken Co., Ltd. (Kagawa, Japan).
The histopathological examinations were performed by
Shikoku Cytopathology Center Co., Ltd. (Kagawa, Ja-
pan). Fixed tissue samples from the liver, kidney, and
small intestine were embedded in paraffin and cut into
sections 5 - 6 m thick on a microtome. The tissue sec-
tions were stai ned with hemat oxylin and eosin ( HE) and
examined by light microscopy. Next, the histopathologi-
cal findings in each rat were subjectively quantified as
follows: –, 0; ±, 1; +, 2; ++, 3; +++, 4.
2.4. Statistical An alysis
All values are expressed as the mean ±SD. Statistical
analysis of the differences between the control and PS
groups was performed using Student’s t-test. Statistical
significance was set at p < 0.05. All analyses were per-
formed with a commercially available statistical soft-
ware package (Excel Statistics 2008; SSRI, Co., Ltd.,

T. Matsuo et al. / Open Journal of Preventive Medicine 1 (2011) 66-71
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJPM/
68
Tokyo, Japan).
3. RESULTS
3.1. Body and Tissue Weights, Food Intake,
and Digestive Tract Size
The body and tissue weights, food intake, and diges-
tive tract size in rats fed the two experimental diets for
Table 2. Body weight, food intake, tissue weights and diges-
tive tract si ze.
Groups Control D-Psicose syrup
Initial weight (g) 60 ± 6 59 ± 5
Final weight (g) 334 ± 19 348 ± 25
Weight gain (g) 274 ± 16 289 ± 22
Food intake (g/day) 19.3 ± 1.1 19.5 ± 0.8
Tissue weights
Brain (g) 1.39 ± 0.33 1.71 ± 0.25
Heart (g) 0.78 ± 0.05 0.82 ± 0.06
Lungs (g) 0.93 ± 0.07 1.00 ± 0.10
Liver (g) 10.4 ± 0.90 10.4 ± 1.34
Pancreas (g) 0.51 ± 0.07 0.55 ± 0.08
Kidneys (g) 2.27 ± 0.18 2.36 ± 0.20
Adrenals (g) 0.05 ± 0.01 0.05 ± 0.01
Spleen (g) 0.72 ± 0.08 0.73 ± 0.06
Testicles (g) 3.10 ± 0.14 3.11 ± 0.11
Intra-adipose tissues1 (g) 21.5 ± 2.79 20.8 ± 4.02
Muscle tissues2 (g) 3.77 ± 0.18 3.91 ± 0.23
Digestive tracts
Stomach weight (g) 1.98 ± 0.49 2.62 ± 0.49
Small intestine weight (g) 5.28 ± 0.48 5.66 ± 0.52
Small intestine length (m) 1.06 ± 0.04 1.10 ± 0.05
Large intestine weight (g) 1.09 ± 0.11 1.09 ± 0.18
Large i ntestine leng th (×10 –2·m)16.9 ± 2.16 18.3 ± 2.36
Cecal weight (g) 0.74 ± 0.15 0.77 ± 0.05
Cecal surface area (×103·mm2)3.76 ± 0.54 4.06 ± 0.40
Values are means ±SD for 10 rats. 1Total weight of epididymal, perirenal
and mesenteric adipose tissues. 2Total weight of soleus , gastrocnemius and
plan taris muscles.
Table 3. Blood hematological an d serum chemical values.
Group Control D-Psicose syrup
Blood
WBC (×102/µl) 30.2 ± 3.0 29.6 ± 4.6
RBC (×104/µl) 89 2 ± 24 892 ± 23
Hb (g/100 ml) 14.4 ± 0.4 14.7 ± 0.5
Ht (%) 46.3 ± 1.4 46.4 ± 1.4
MCV (fl) 52.0 ± 1.0 52.0 ± 1.0
MCH (pg) 16.2 ± 0.2 16.4 ± 0.3
MCHC (%) 31.2 ± 0.6 31.6 ± 0.5
PLT (×104/µl) 56.6 ± 8.5 56.1 ± 2.0
Serum
TP (g/100 ml) 6.23 ± 0.18 6.15 ± 0.20
A/G 3.17 ± 0.49 3.04 ± 0.34
ALBU (g/100 ml) 4.72 ± 0.25 4.62 ± 0.21
GLO (g/100 ml) 1.51 ± 0.15 1.53 ± 0.13
TBI L (mg/100 ml ) 0.20 ± 0.0 0 0. 20 ± 0.00
DBIL (mg/ 10 0 ml) 0.10 ± 0.0 0 0. 10 ± 0. 0 0
IBIL (mg/100 ml) 0.10 ± 0.0 0 0. 10 ± 0.00
AST (IU /I) 230 ± 32 172 ± 92
ALT (IU/I) 76.1 ± 19.4 87.9 ± 48.2
UA (mg /10 0 m l ) 1.22 ± 0.2 6 1. 14 ± 0.36
BUN (m g /10 0 m l ) 20 .8 ± 1.7 22.2 ± 2.1
CREA (mg/100 m l ) 0.27 ± 0.0 3 0. 30 ± 0.05
Ca ( mg/100 ml ) 10 .2 ± 0.2 10.4 ± 0.3
Fe (µg/100 ml) 110 ± 25 111 ± 13
CHO (m g /10 0 ml) 70.1 ± 10.0 68.8 ± 12.5
TG (mg/100 ml) 79.6 ± 36. 1 69.0 ± 32.4
GL U (mg/10 0 m l ) 156 ± 14 167 ± 14
FFA (mEq/100 ml)0.87 ± 0.24 0.70 ± 0.11
Values are means ±SD for 10 rats.
90 days are presented in Table 2. T he final body weight,
weight gain, and food intake did not differ between the
control and PS groups. The mean stomach and cecal
content weights were significantly higher in the PS
group than in the control group, but no differences were
observed in any other tissues.
3.2. Serum Chemical and Blood
Hematological Values
No differences were observed in any chemical or he-
matological values between the control and PS groups
(Table 3). These values remained within the normal
ranges, indicating that there was no overt PS toxicity.
3.3. Histopathological Examination
The histopathological observations of the liver, kidney,

T. Matsuo et al. / Open Journal of Preventive Medicine 1 (2011) 66-71
Copyright © 2011 SciRes. http://www.scirp.org/journal/OJPM/Openly accessible at
69 69
and small intestine are presented in Table 4. Age-related
naturally-occurring lesions were observed in the tissues,
but no abnormalities due to the ingestion of PS were
observed. The histopathological examination showed no
differences i n the total damage in the li ver, kidneys, and
small intestine between the control and PS groups.
4. DISCUSSION
In the present 90-day feeding study of PS at a dose of
4.3% in male Wistar rats, no mortality occurred, and
systemic toxicity wa s not evident. We have examined the
effects of acute [11], sub-chronic (90 days) [15], and
long-term feeding (12 - 18 months) [14] of D-psicose to
rats prior to its u tilization as a physiologically functional
food. We concluded that a small amount of D-psicose in
the diet had no adverse effects in rats. In the present
study, we focused on the safety of impurities (0.5% un-
known ingredients) of the PS rather than safet y of the PS
itself. Therefore, the control diet included 0.5% sucrose
for comparison with 0.5% impurities in the PS diet.
Generally, small amounts of impurities are included in
natural products and processed foods [19]. For example,
royal jelly has been widely used as a dietary supplement
and in cosmetics in many countries [20]. With regard to
chemical composition, ro yal jelly was reported to consist
mainly of proteins, sugars, lipids, vitamins, and many
unknown ingredients [21,22]. The main active ingredi-
ents of royal jelly are not clear, but royal jelly is recog-
nized as a safe food or supplement [23]. On the other
hand, HFCS also contains about 6% unknown ingredi-
ents [24]. However, HFCS has already been generally
used in many developed countries [25]. PS includes un-
Table 4. Histopathological observations of liver, kidney and small intestine1.
Groups Control D-Psicose syrup
Ogans Findings
Liver Bile duct proliferation 0.0 ± 0.0 0.0 ± 0.0
Necrosis 0.2 ± 0.4 1.9 ± 1.0
Microgranuloma 0.4 ± 0.5 1.2 ± 1.0
Lipid deposition 0.0 ± 0.0 0.0 ± 0.0
Fatty change 0.0 ± 0.0 0.0 ± 0.0
Total score of damage 0.6 ± 0.7 3.1 ± 1.4
Kidney Basophilic change in the tubule 1.0 ± 1.3 1.2 ± 1.2
Hyaline cast in the tubule 0.8 ± 0.8 1.0 ± 0.8
Brown pigment deposition in the tubule 0.0 ± 0.0 0.0 ± 0.0
Atrophy of the glomerulus 0.0 ± 0.0 0.0 ± 0.0
Hyalinization in the glomerulus 0.0 ± 0.0 0.0 ± 0.0
Thickening of Bowman’s capsule basement membrane0.0 ± 0.0 0.0 ± 0.0
Lymphocyte infiltration in the interstitium 0.2 ± 0.4 0.4 ± 0.5
Total score of damage 1.5 ± 1.3 2.0 ± 1.5
Small intestine Villous damage 0.4 ± 0.7 1.2 ± 1.0
Crypt damage 0.1 ± 0.3 0.4 ± 0.5
Cellular infiltration 0.9 ± 0.6 0.8 ± 0.9
Goblet cell depletion 0.1 ± 0.3 0.5 ± 0.9
Total score of damage 1.5 ± 1.7 2.9 ± 2.2
Values are means ±SD for 10 rats. 1Quantify the findings level of damage in each rats: –, 0; ±, 1; +, 2; ++, 3; +++, 4.

T. Matsuo et al. / Open Journal of Preventive Medicine 1 (2011) 66-71
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70
known impurities, but it is likely to be a safe food prod-
uct. The PS was made from HFCS by the alkaline isom-
erization method. The alkaline isomerization method is
used widely, resulted in production of many sugar prod-
ucts, such as cyclodextrin, maltitol, and erythritol [26] .
D-Psicose can be produced by the enzymatic method
on a large scale, making it possible to conduct bio-
chemical and nutritional studies [6]. We found that D-
psicose is a sweet monosaccharide that provides no en-
ergy and leads to less body fat accumulation than D-
gluco se a nd D-fructose in rats [7,8]. In addition, we have
suggested that supp lemental D-psicose can lower plasma
gluco se le vels [ 9]. D-Psicose is expected to have a bene-
ficial effect in the control of blood glucose levels in type
2 diabetes. However, D-psicose is more expensive than
other substitute sugars. However, PS can be produced
more easily and cost-effectively than D-psicose. PS ma y
be effective for the prevention obese or type 2 diabetes
as functional foods.
In conclusion, the present study evaluated the effects
of 90-day 4.3% PS administration to rats, and there were
no gross pathological findings. The hematological and
chemical values were not suggestive of any overt PS
toxicity. Overall, no adverse effects were seen at this low
dose level of PS in the diet.
5. ACKNOWLEDGEMENTS
We would like to thank Dr. Koji Kondo, Rare Sugar Production
Technical Research Laboratories, LLC (Kagawa, Japan) for donating
D-psicose. This work was supported by the Regional Innovation Crea-
tion R&D Programs, Ministry of Economy, Trade and Industry, Japan.
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