Of the more than 360 Aloe species known, Aloe barbaden-
sis MILLER (Aloe vera) is the most widely used. Aloe vera
contain two major parts: firstly, leaves containing a high con-
centration of anthraquinone compounds that have been used
throughout the centuries as a cathartic and for medicinal
purges; and secondly, a clear gel that has been used as a food
and to treat burns and other wounds.1,2)
Several chemical components of the Aloe gel are thought
to be responsible for its wound healing and immunostimula-
tory properties. For example, glycoprotein Aloectin A is re-
ported to have anti-tumor and anti-ulcer effects,3)and a 29
kDa glycoprotein has been found to increase proliferation of
normal human dermal cells.4)Most of these polysaccharides
are glucomannans, mannans, or pectins with a range of mo-
lecular weights. A major focus of research has been on the
carbohydrate fraction isolated from Aloe gel known as “ace-
mannan,” which comprises a polydispersed b-(1,4)-linked
acetylated mannan interspersed with O-acetyl groups.5)
As a result of these studies, there have been numerous re-
ports of Aloe having diverse biological activities, including
anti-tumor activity, anti-acid activity,6)tyrosinase inhibiting
activity,7)and antioxidant activity.8)
Two clinical trials are available from the same research
group that reported hyperglycemic effects on fasting blood
glucose as well as on HbA1c levels9,10)with Aloe vera gel.
Hikino et al. isolated two hyperglycemic polysaccharides
from Aloe arborescens at 1985.11)Beppu et al. separated two
different anti-diabetic components from the leaf pulp and
leaf skin of the same plant. A previous study made with Ki-
dachi Aloe (Aloe arborescens var. naralensis) in streptozo-
tocin (STZ)-induced diabetic rats confirmed its efficacy
through administration,12)contrary to Koo who reported hy-
perglycemic effects in diabetic rats in acute phase with a
product containing Aloe vera gel.13)
In this study, we sought to determine the constituents of
Aloe vera gel extract that normalize hyperglycemia in the di-
abetic mouse strain BKS.Cg-m?/?Leprdb/J(db/db), which ex-
hibits many of the metabolic disturbances of human type 2
diabetes including hyperglycemia, obesity, and insulin resist-
ance. Hemoglobin A1c (HbA1c), a binding product of glu-
cose and hemoglobin, increases depending on the severity of
hyperglycemia in a glucose level-dependent manner, and the
level of HbA1c reflects the past blood glucose control condi-
tions over a long period. Therefore, we tried to isolate the
bioactive compounds from Aloe vera gel based on their abil-
ity to decrease the HbA1c level of db/db mice. Finally, we
examined whether phytosterols and fractions isolated from
Aloe vera gel play an important role in anti-hyperglycemic
MATERIALS AND METHODS
a micro melting point apparatus (Yanako MP-3) without cor-
rection. NMR spectra were recorded using a Varian Unity-
500 spectrometer (13C: 125MHz). Positive APCI-MS was
taken with LC-MS 2000 (Shimadzu).
Preparation of Extracts
(1kg) were extracted three times with CHCl3/MeOH (1l
each) at room temperature for 1h, and separated into a
CHCl3/MeOH soluble fraction (T1 extract, 0.5g) and an H2O
layer. The H2O layer was further extracted three times with n-
BuOH (1l each) at room temperature for 3h, and separated
into a n-BuOH soluble fraction (T2 extract, 0.5g) and an
Melting points were determined on
Fresh leaf gels of Aloe vera
1418Vol. 29, No. 7
Biol. Pharm. Bull. 29(7) 1418—1422 (2006)
Identification of Five Phytosterols from Aloe Vera Gel as Anti-diabetic
Miyuki TANAKA,*,aEriko MISAWA,aYousuke ITO,aNoriko HABARA,aKouji NOMAGUCHI,a
Muneo YAMADA,aTomohiro TOIDA,aHirotoshi HAYASAWA,aMitunori TAKASE,a
Masanori INAGAKI,cand Ryuuichi HIGUCHIc
aBiochemical Research Laboratory, Morinaga Milk Industry Co., Ltd.; 5–1–83 Higashihara, Zama, Kanagawa 228–8583,
Japan: and bFaculty of Pharmaceutical Sciences, Kyushu University; 3–1–1 Maidashi, Higashi-ku, Fukuoka 812–8582,
Received February 20, 2006; accepted April 7, 2006; published online April 11, 2006
The genus Aloe in the family Liliaceae is a group of plants including Aloe vera (Aloe barbadensis MILLER)
and Aloe arborescens (Aloe arborescens MILLER var. natalensis BERGER) that are empirically known to have vari-
ous medical efficacies. In the present study, we evaluated the anti-hyperglycemic effect of Aloe vera gel and iso-
lated a number of compounds from the gel. On the basis of spectroscopic data, these compounds were identified
as lophenol, 24-methyl-lophenol, 24-ethyl-lophenol, cycloartanol, and 24-methylene-cycloartanol. These five phy-
tosterols were evaluated for their anti-hyperglycemic effects in type 2 diabetic BKS.Cg-m?/?Leprdb/J(db/db)
mice. In comparison with the hemoglobin A1c (HbA1c) levels of vehicle-treated mice, statistically significant de-
creases of 15 to 18% in HbA1c levels were observed in mice treated with 1m mg of the five phytosterols. Consider-
ing the ability to reduce blood glucose in vivo, there were no differences between the five phytosterols. Adminis-
tration of b b-sitosterol did not reduce the blood glucose levels in db/db mice. After administration of the five phy-
tosterols for 28d, fasting blood glucose levels decreased to approximately 64%, 28%, 47%, 51%, and 55% of
control levels, respectively. Severe diabetic mice treated with phytosterols derived from Aloe vera gel did not suf-
fer weight reduction due to glucose loss in the urine. These findings suggest that Aloe vera gel and phytosterols
derived from Aloe vera gel have a long-term blood glucose level control effect and would be useful for the treat-
ment of type 2 diabetes mellitus.
Aloe vera gel; type 2 diabetes; phytosterol
© 2006 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed.e-mail: firstname.lastname@example.org
H2O layer. The H2O layer was concentrated under reduced
pressure followed by lyophilization to give the T3 extract
(2.4g). The T3 extract (2g) was extracted three times with
MeOH (200ml each) at room temperature for 2h, and sepa-
rated into a MeOH layer and an insoluble mass (T5 extract,
14g). Evaporation of the combined MeOH solution afforded
the T4 extract (2.5g).
Preparation of Compounds
was extracted three times with CHCl3/MeOH (90l). The
CHCl3/MeOH fraction (784g) was subjected to silica gel
column chromatography eluted with a gradient system of
CHCl3/MeOH (10:1→1:10) to provide 5 fractions. Frac-
tion 1 (132.7g) was further purified by silica gel column
chromatography eluted with a gradient system of AcOEt/n-
hexane (1:20→1:10) to provide 6 fractions (B1—B6).
Fraction B1 (4g) was further purified on a SP-120-40/
60-ODS-A column eluted with MeOH/MeCN/THF/H2O
(76.5:10:9:4.5) to provide crude B11 and B12 fractions.
The crude B11 and B12 fractions were isolated on an Inertsil
ODS-3 column eluted with MeOH/MeCN/THF/H2O (15:
2:2:1) and purified by chromatography on a silica gel col-
umn using AcOEt/n-hexane (1:10) as the eluent to give puri-
fied compounds of B11 (228mg) and B12 (197mg).
B11: Amorphous powder, mp 100—101°C. Positive APCI-
MS exhibited m/z 411 [M?H?H2O]?, 429 [M?H]?. The
structure of B11 was determined as cycloartanol on the basis of
13C-NMR spectral data by comparison with literature values.14)
B12: Amorphous powder, mp 118—120°C. Positive APCI-
MS exhibited m/z 423 [M?H?H2O]?. The structure of B12
was determined as 24-methylene-cycloartanol on the basis of
13C-NMR spectral data by comparison with literature values.14)
The crude B2 fraction was purified by chromatography on
a silica gel column using AcOEt/n-hexane (1:10) as the elu-
ent to give purified compounds of B2 (80.5g). B2 was identi-
fied by direct comparison (13C-NMR) with an authentic sam-
ple of b-sitosterol.
Fraction B3 was mixed with dry-pyridine (35ml), DMAP
(12.3mg), and acetic anhydride (10ml) and reacted for 15h
at room temperature. The reaction mixture was diluted with
H2O, extracted with CHCl3, and the solvent was evaporated.
An acetyl derivative of fraction B3 (257g) was purified by
SP-120-40/60-ODS-A column chromatography and eluted
with MeoH/MeCN/THF/H2O (17:2:2:1) to provide three
crude compounds (acetyl-B31, acetyl-B32 and, acetyl-B33).
These crude compounds were further purified by Inertsil
ODS-A column chromatography and eluted with MeOH/
MeCN/THF/H2O (16:2:2:1). The acetyl derivatives of the
three compounds were added to a mixture of THF (150ml),
MeOH (300ml), H2O (100ml), and K2CO3(1g). Each mix-
ture was heated to 50°C for 18h and then extracted with
CHCl3to isolate compounds B31 (89mg), B32 (125mg),
and B33 (4mg), respectively.
B31: Amorphous powder, mp 151—152°C. Positive APCI-
MS exhibited m/z 383 [M?H?H2O]?. The structure of B31
was determined as lophenol on the basis of 13C-NMR spec-
tral data by comparison with literature values.14)
B32: Amorphous powder, mp 174—175°C. Positive APCI-
MS exhibited m/z 397 [M?H?H2O]?. The structure of B32
was determined as 24-methyl-lophenol on the basis of 13C-
NMR spectral data by comparison with literature values.14)
B33: Amorphous powder, mp 168—169°C. Positive APCI-
Dried Aloe vera (21kg)
MS exhibited m/z 411 [M?H?H2O]?. The structure of B33
was determined as 24-ethyl-lophenol on the basis of 13C-
NMR spectral data by comparison with literature values.14)
Animals and Treatment
into small pieces and homogenized with PBS in a blender.
The final concentration of Aloe vera gel was adjusted to ei-
ther 20, 30, or 50mg/ml. Extracts and compounds were dis-
solved in DMSO (Sigma), and the concentration of each
compound, extract, or fraction was adjusted to 1mg/ml or
25mg/ml with saline, respectively. The final concentration of
DMSO was adjusted to 0.1%. Saline containing 0.1% DMSO
was used as the vehicle. As a type 2 diabetes model, 6-week
old male BKS.Cg-m?/?Leprdb/J(db/db) mice were obtained
from Charles River Japan (Tokyo, Japan). The mice were di-
vided into several groups each consisting of 7 mice, and ad-
ministered orally with vehicle as a control solution, 1mg/
mouse/d of a compound, or 25mg/mouse/d of an extract or
Measurement of Blood Glucose
levels and random blood glucose levels were measured by
using an Antsense analyzer (Bayer-Sankyo, Tokyo, Japan).
The fasting blood glucose levels were measured after 15h of
fasting. HbA1C levels were measured using a DCA2000 ana-
Immunostaining of Islets
treated with Aloe vela gel or vehicle were excised, fixed by
immersion in 4% buffed formaldehyde, and then embedded
in paraffin. Paraffin sections were incubated for 10min with
3% H2O2solution to block endogenous peroxidase activity
and then overnight at 4°C with guinea pig anti-insulin anti-
body (Dako Diagnostics, Missisauga, CA, U.S.A.). Sections
were then incubated for 1 h with biotinylated anti-guinea pig
antibody (Vector Laboratories, Berlingame, CA, U.S.A.),
subsequently treated for 30min with an avidin/biotin com-
plex (Vectastain ABC kit, Vector Laboratories, Berlingame,
CA, U.S.A.), and positive reactions were visualized by incu-
bation with a peroxidase substrate solution containing 3,3?-
Data is presented as the mean?S.D. Statistical
significance was assessed by group comparison with the use
of one-way ANOVA followed by Tukey–Kramer test. Signifi-
cance was accepted at p?0.05.
Fresh Aloe vera gel was cut
Fasting blood glucose
Pancreases from db/db mice
Previous reports demonstrated that Aloe vera gel extract
has a protective effect comparable to glibenclamide against
hepatotoxicity in neonatal streptozotocin (n0STZ)-induced
July 2006 1419
Vera Gel or Saline
Fasting Blood Glucose Levels of db/db Mice Treated with Aloe
Fasting blood glucose levels (mg/dl)
Day 0 Day 15Day 29
Aloe vera gel 20 mg
Seven db/db mice each were daily administered orally with saline or the indicated
dose of Aloe vera gel and fasting blood glucose was measured on Day 15 and Day 29.
Significantly different from saline-injected mice (∗p?0.05 and ∗∗p?0.005).
type-II diabetic rats.14)Okyar et al. reported that Aloe vera
gel extract showed hyperglycemic activity in NIDDM (Non-
Insulin Dependent Diabetes Mellitus) rats.15)Therefore, we
tried to administer type 2 diabetes model mice with Aloe
vera gel. After administration for 15d, fasting blood glucose
levels of mice treated with 10, 20, or 30mg/mouse/d of Aloe
vera gel were reduced to 88%, 58%, and 54% respectively, of
the control level (Table 1). On day 29, fasting blood glucose
levels of mice treated with Aloe vera gel were decreased sig-
nificantly compared to controls (p?0.05 and p?0.005). On
day 35, when pancreas tissue was stained with anti-insulin
antibodies, those of db/db mice treated with 50mg/mouse/d
of Aloe vera gel exhibited strong staining (Fig. 1B), as com-
pared with the pancreas tissue of control littermates (Fig.
1420 Vol. 29, No. 7
In saline-treated mice (A), islets were irregular in shape and weak immunostaining
was observed. In contrast, islets from mice treated with 50mg/mouse/d of Aloe vera
gel (B) showed intense insulin immunostaining. Bar, 200mm.
Immunostaining for Insulin in Pancreas of db/db Mice
Seven db/db mice each were daily administered orally with 0.1% DMSO as the con-
trol solution or 1mg of compound or 25mg/mouse/d of extract/fraction. Significantly
different from vehicle-injected mice (∗p?0.05 and ∗∗p?0.005).
The in Vivo Effects of Compounds Derived from Aloe Vera Gel on
Isolation Method for Anti-hyperglycemic Compounds from Aloe
Seven db/db mice each were daily administered orally with 0.1% DMSO as the control solution or 1mg/mouse/d of
B11, B12, B2, B31, B32, B33, or 25mg/mouse/d of B4, B5, B6, or T1. Significantly different from vehicle-injected
mice (∗p?0.05 and ∗∗p?0.005).
Phytosterols Derived from Aloe Vera Gel Prevented the Development of Diabetes in db/db
pounds B11, B12, B31, B32, and B33
Chemical Structures of Com-
1A). The size of islets derived from saline-treated mice ap-
peared smaller than those derived from mice treated with
Aloe vera gel. The number of islets derived from mice
treated with 20mg/mouse/d of Aloe vera gel for 35d was
1.7-fold higher than from saline-treated mice (data not
Fresh Aloe vera gel was homogenized with CHCl3/MeOH
(2:1) solution in a mixer and divided into CHCl3/MeOH and
H2O layers. Part of the H2O layer was successively divided
into a n-BuOH extract or a MeOH layer. Finally, five extracts
were separated from Aloe vera gel by the procedures shown
in Fig. 2, and were separately administered to db/db mice.
When evaluated after the administration of T1 extract
(25mg/mouse/d) for 12d, the fasting blood glucose level was
significantly reduced to 85% of the controls, but the other
four extracts did not exhibit the ability to reduce the blood
glucose level of db/db mice (data not shown). After 35d, ad-
ministration of T1 extracts (25mg/mouse/d) caused a reduc-
tion in HbA1c levels (Fig. 3A). Therefore, anti-diabetic com-
pounds were found to be concentrated in the T1 extract. The
T1 fraction was subjected to normal-phase silica gel column
chromatography and was divided into 5 fractions (F1—F5).
After 29d, the HbA1c levels of db/db mice administered
with 25mg/mouse/d of F1 or F3 were 1.3% and 1.2%, re-
spectively, lower than mice administered with vehicle (Fig.
We attempted to isolate the effective compounds from F1.
F1 was subjected to normal-phase silica gel column chro-
matography and divided into six fractions (B1—B6). Frac-
tions B1, B2, and B3 were further purified by chromatogra-
phy to give six compounds. As shown in Fig. 4, the struc-
tures of the six compounds were identified as phytosterols by
detailed 13C-NMR spectroscopy and by comparison of the
spectral data with that of published values.16)
We next examined whether in vivo treatment with phyto-
sterols and other fractions decreased the blood glucose levels
of db/db mice. The results of HbA1c level measurements on
the 35th day from the start of administration with 1mg/
mouse/d of B11, B12, B2, B31, B32, or B33 and 25mg/
mouse/d of B4, B5, B6, or T1 are shown in Fig. 3C. In com-
parison with the HbA1c levels of mice treated with vehicle a
statistically significant decrease of 15 to 18% was observed
in mice treated with 1mg/mouse/d of the five phytosterols de-
rived from fraction B1 or fraction B3. The decreases caused
by other fractions or B2 (b-sitosterol) were found to be in-
Blood glucose levels of db/db mice treated chronically
with the five phyotsterols are shown in Fig. 5. In serious dia-
betic model mice, 1mg/mouse/d of chronic phytosterols de-
rived from Aloe vera gel resulted in a decrease in both levels
of fasting blood glucose and random blood glucose com-
pared to vehicle controls, reaching statistical significance
from Day 4 or Day 5 (Figs. 5A, B). After administration for
28d, fasting blood glucose levels were decreased to approxi-
mately 64%, 28%, 47%, 51%, and 55% of the control levels,
by administration of 1mg/mouse/d of B11, B12, B31, B32,
and B33, respectively. In comparison with the blood glucose
levels of mice treated with vehicle, there was no difference in
the blood glucose levels of mice treated by B2 (b-sitosterol)
We observed a decrease of body weight in vehicle-treated
mice, but not in mice treated with Aloe vera gel or its com-
ponents (Table 2) over the course of the experiment. While
weights of the groups were similar on Day 0, following the
33d of the experiment, the vehicle-treated mice weighted on
average approximately 2.9 to 6.4g less than the mice treated
with Aloe vera gel or its components.
Previous studies demonstrated that an alcoholic extract of
Aloe vera gel maintained the glucose homeostasis of strepto-
zotocin-induced diabetic rats by controlling the carbohydrate
metabolizing enzymes.17)However, little is known about the
structures of the active compounds in Aloe vera gel. The
present study, in which we identified five minor phytosterols,
should help us to comprehend the anti-diabetic mechanisms
of Aloe vera gel.
b-Sitosterol, campesterol, and stigmasterols are abundant
plant sterols and are structurally similar to cholesterol. It was
recognized in the 1950s that plant sterols lower serum con-
centrations of cholesterol. They do this by reducing the ab-
sorptions of cholesterol from the gut by competing for the
limited space for cholesterol in mixed micelles.18.19)
In this study, we observed that 1mg of phytosterols de-
rived from Aloe vera gel lower blood glucose levels; how-
ever, we did not observe the reduction of serum concentra-
tions of cholesterols (data not shown). This may be simply
explained by presuming that the effective dose that was ap-
plicable to decrease serum cholesterol levels was more than
100-fold higher than that applicable to decrease blood glu-
cose levels.20)It was also possible that the effective structure
for the reduction of serum cholesterol was the 4-desmethyl
moiety (containing no methyl groups at carbon atom 4),
while the structures of anti-hyperglycemic phytosterols de-
rived from Aloe vera gel were 4-monomethyl and 4-dimethyl
In considering structure, the anti-hyperglycemic phyto-
sterols derived from Aloe vera gel fall into two groups of
compounds, the lophenol group and the cycloartane group.
Lophenol is known to be an intermediate of the biosynthetic
pathway for squalane in plants21); however, the effect of this
compound in vivo is unknown. A previous report suggested
that compounds with a cycloartane structure e.g., cycloar-
tanol, had the ability to prevent cancer.22)However, the effect
July 2006 1421
on Body Weight Loss in Severe Diabetic Mice
Preventative Effects of Phytosterols Derived from Aloe Vera Gel
Body weight (g)
Day 0Day 33
Aloe vera gel 50mg
Seven db/db mice each were daily administered orally with 0.1% DMSO as the con-
trol solution or 1mg/mouse/d of compound or 25mg/mouse/d of T1 extract. Signifi-
cantly different from vehicle-injected mice (∗p?0.05).
of cycloartane compounds on diabetes mellitus was un-
As shown in Fig. 3B, anti-hyperglycemic effects were also
observed in fraction 3. We tried to isolate and purify the ac-
tive compounds from fraction 3, and obtained two crude frac-
tions. Because both compounds showed a Rf values very
close to that of b-sitosterol glucoside in an examination
based on TLC, it was anticipated to be a glycoside in which
one molecule of sugar was bound to the aglycon moiety. To
examine the sugar composition of the methanolysis product,
it was made into a Trimethylsilyl (TMS) derivative and sub-
jected to GC-MS measurement. The main peaks were sub-
stantially consistent with the main peaks of authentic glucose
(data not shown). After the crude glycosides were
methanolyzed and acetylated, these agflycons were isolated.
The aglycon moieties coincided with 24-methyl-lophenol
and 24-ethyl-lophenol by detailed 1H- and 13C-NMR spec-
troscopy (data not shown).
This study demonstrated that long-term treatment with
Aloe vera gel ameliorates hyperglycemia in diabetic C57BL/
KS-Lepdb(db/db) mice, where the mice lack functional leptin
receptor.23,24)In this strain of mice, metabolic abnormalities
manifest early during development and are quite severe in
young adult animals. Moreover, once established, these meta-
bolic changes are resistant to modulation by caloric restric-
tion or weight reduction compared with other mouse models
of obesity-associated insulin resistance and dyslipidemia.25)
We observed weight reduction in vehicle-treated mice in line
with previous reports (Table 2). In contrast, the mice treated
with Aloe vera gel or its effective compounds did not experi-
ence weight reduction. This differential body weight re-
sponse most likely reflects the more severe hyperglycemia of
the vehicle-treated mice, which will lose more calories due to
glucose loss in the urine.
Administration of phytosterols derived from Aloe vera gel
did not change the blood glucose levels in a normal
C57BL/6J mouse (data not shown). In addition, the pre-ad-
ministration of phytosterols did not change the glucose toler-
ance of normal mice (data not shown).
It is well known that mice fed a high fat diet develop obe-
sity and hyperglycemia and are used as a model of nonin-
sulin-dependent diabetes mellitus.26)We have evaluated the
effects of Aloe vera gel in high fat diet-fed obese mice. Ad-
ministration of Aloe vera gel with the high fat diet prevented
the development of insulin resistance and glucose intolerance
(data not shown). Further studies are required to determine
the molecular basis of the effect of anti-diabetic phytosterols
on the normalization of insulin resistance and glucose intol-
There was no case showing acute hypoglycemic conditions
during the administration of Aloe vera gel or its anti-diabetic
compounds, and no adverse side effect symptoms were ob-
served from the viewpoints of pathological findings. Thus,
the phytosterols derived from Aloe vera gel could be useful
compounds for the treatment or preventor of type 2 diabetes
Dr. M. Ito of the Technical Research Center of T. Hasegawa
The authors thank Dr. A. Fujita and
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