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OBJECTIVE— To
investigate the
tolerability, efficacy,
and mode of action of
Caiapo, an
extract of white sweet
potatoes, on metabolic
control in type 2
diabetic patients.
RESEARCH DESIGN AND
METHODS— A total of 61
type 2 diabetic patients
treated
by diet were given 4 g
Caiapo (n 30; mean age
55.2 2.1 years; BMI 28.0
0.4 kg/m2) or
placebo (n 31; mean age
55.6 1.5 years; BMI 27.6
0.3 kg/m2) once daily
for 12 weeks.
Each subject underwent a
75-g oral glucose
tolerance test (OGTT) at
baseline and after 1, 2,
and
3 months to assess 2-h
glucose levels.
Additionally, fasting
blood glucose, HbA1c,
total cholesterol,
and triglyceride levels
were measured.
RESULTS— After treatment
with Caiapo, HbA1c
decreased significantly
(P 0.001) from
7.21 0.15 to 6.68 0.14%,
whereas it remained
unchanged (P 0.23) in
subjects given
placebo (7.04 0.17 vs.
7.10 0.19%). Fasting
blood glucose levels
decreased (P 0.001) in
the Caiapo group (143.7
1.9 vs. 128.5 1.7 mg/dl)
and did not change in
the placebo group
(144.3 1.9 vs. 138.2 2.1
mg/dl; P 0.052). A
decrease in body weight
was observed in both
the placebo group (P
0.0027) and in the
Caiapo group (P 0.0001),
probably due to a
bettercontrolled
lifestyle. In the Caiapo
group, body weight was
related to the
improvement in glucose
control (r 0.618; P
0.0002). Two-hour
glucose levels were
significantly (P 0.001)
decreased in the Caiapo
group (193.3 10.4 vs.
162.8 8.2 mg/dl)
compared with the
placebo
group (191.7 9.2 vs.
181.0 7.1 mg/dl). Mean
cholesterol at the end
of the treatment was
significantly lower in
the Caiapo group (214.6
11.2 mg/dl) than in the
placebo group (248.7
11.2 mg/dl; P 0.05). No
significant changes in
triglyceride levels or
blood pressure were
observed, and Caiapo was
well tolerated without
significant adverse
effects.
CONCLUSIONS— This study
confirms the beneficial
effects of Caiapo on
plasma glucose as
well as cholesterol
levels in patients with
type 2 diabetes. For the
first time, the
long-term efficacy
of Caiapo on glucose
control was demonstrated
by the observed decrease
in HbA1c. Thus, the
neutraceutical Caiapo
seems to be a useful
agent in the treatment
of type 2 diabetes. The
pathogenesis of type 2
diabetes
involves insulin
resistance and impaired
insulin secretion (1,2).
When
diet therapy and
exercise remain
ineffective,
medications such as oral
hypoglycemic
drugs or insulin must be
used (3,4).
In addition to insulin
and drugs that stimulate
insulin release, new
compounds
that improve insulin
sensitivity are
currently
under investigation or
are already
in clinical use (4 –7).
Recently, attention
has also been directed
to evaluate the efficacy
of natural and
neutraceutical products
on diabetes control (8
–10). As noted
in a recent
meta-analysis on
neutraceuticals
in management of
diabetes, few compounds
have shown efficacy in
randomized trials (11).
However, in the
absence of thoroughly
controlled studies
on effectiveness and
potential risks, these
neutraceuticals cannot
be unanimously
recommended for
management of diabetes
(12,13).
A variety of white sweet
potato cultivated
in a mountainous region
of Kagawa
Prefecture, Japan, has
been eaten raw for
many years in the belief
that it is effective
therapy for anemia,
hypertension, and
diabetes.
Caiapo (Ipomoea batatas)
is commercialized
in Japan without medical
prescription as a food
additive
(neutraceutical)
for the prevention and
care of
type 2 diabetes (14,15).
In a previous
study, we evaluated the
efficacy and
tolerability
of two doses (2 and 4
g/day) of
Caiapo versus placebo
given orally for 6
weeks to 18 male
Caucasian patients with
type 2 diabetes treated
only by diet (16).
Those results showed
that Caiapo at the
dose of 4 g/day for 6
weeks lowered total
and LDL cholesterol
levels, as well as blood
glucose, by increasing
insulin sensitivity
without affecting
insulin secretion.
The low number of
subjects and the
short duration of the
prior study prevented
us from evaluating the
effect of Caiapo
on parameters of
long-term glucose
control such as HbA1c.
Thus, it seemed of
clinical and scientific
interest to verify
those findings in a
wider comparative
trial. The aim of the
present study was,
therefore, assessment of
the efficacy and
tolerability of Caiapo
(4 g/day) compared
with placebo when
administered for 12
consecutive weeks to
type 2 diabetic patients
with mild fasting
hyperglycemia
who were advised to keep
body weight,
physical activity, and
diet under control
during the entire study
period. RESEARCH DESIGN
AND
METHODS— This
investigation was
performed in a total of
61 clinically stable
type 2 diabetic patients
treated by diet
only and recruited from
the offices of general
practitioners. In five
patients, the respective
antidiabetic medication
(metformin,
glibenclamide,
glimepiride)
was withdrawn 2 weeks
before the start of
the study. All of these
patients gave informed
consent to participate
in this
study, which was
approved by the Ethics
Committee of the Swiss
Federal Authorities
(IKI). All patients had
no relevant history
of renal, hepatic,
cardiovascular,
hematological,
respiratory, autoimmune,
or neurological
diseases. Apart from
diabetes,
no other endocrine
dysfunction
that could interfere
with the study was
detected. Subjects were
instructed to follow
a weight-maintaining
diet (28 –32
kcal/kg body wt)
consisting of 55%
carbohydrates,
30% fat, and 15%
proteins.
Drinking alcohol and
smoking cigarettes
were allowed if patients
were in the habit
of doing so, but alcohol
consumption was
limited to 60 g/day for
men and 40 g/day
for women and smoking
was limited to 10
cigarettes/day. Each
subject was advised
to maintain usual
physical activity at a
constant level
throughout the entire
period
of the study.
The study was
placebo-controlled,
randomized, and
double-blinded. Patients
were randomly divided
into two
groups: group 1 (n 30)
consumed Caiapo
4 g/day, and group 2 (n
31) consumed
placebo. After
disclosure of the
randomization code, data
of both groups
showed no differences in
baseline parameters,
except for glucose
levels measured
2 h after dinner (Tables
1 and 2). Both
Caiapo and placebo were
taken orally
once daily, in the
morning before
breakfast.
Each subject underwent a
75-g oral
glucose tolerance test
(OGTT) in the
clinic at baseline and
after 1, 2, and 3
months. Fasting and 2-h
glucose levels
were measured from
venous samples (15
ml) by the glucose
oxidase method. Subjects
measured their blood
glucose levels
at home using a blood
glucose test system
(Glucotrend; Boehringer
Mannheim,
Mannheim, Germany). All
patients were
instructed regarding use
of the glucometer,
and the subjects’
ability to correctly
use the glucometer, as
well as instrument
precision and
calibration, were
frequently
checked. Blood glucose
levels were monitored
three times per week: on
Monday
before breakfast, on
Wednesday 2 h after
beginning lunch, and on
Friday 2 h after
beginning dinner. These
measurements
were averaged over 1
month. HbA1c was
measured by immunoassay
(IMX; Abbott,
North Chicago, IL);
cholesterol and
triglyceride
levels were measured by
routine
laboratory methods.
Statistics
Changes in blood
glucose, total
cholesterol,
triglyceride, and HbA1c
values after
treatment were analyzed
between groups
by ANOVA using
corresponding baseline
values and BMI as
covariates. Comparisons
versus baseline were
assessed within
groups with the
appropriate Student’s t
test corrected by
Bonferroni adjustment.
Coefficient of
correlation was
calculated
for changes in HbA1c
versus changes in
weight. Unless otherwise
specified, data
are reported as means
SE.
Tolerability and safety
Tolerability scores were
compared between
groups using 2 test. The
safety
analysis was performed
in all randomized
patients to assess the
nature, severity, and
frequency of adverse
effects, including
laboratory values
outside the normal
range that may suggest a
clinically relevant
abnormality. The
equivalence between
the two groups
concerning
occurrence of adverse
effects was assessed
using 2 test.
RESULTS
HbA1c
After treatment with
Caiapo, HbA1c
significantly
decreased after 2 and 3
months
(Table 2); no change was
observed in the
placebo group (P 0.08
after 2 months
and P 0.23 after 3
months versus baseline).
At both 2 and 3 months,
HbA1c values
in the Caiapo group were
lower than
the corresponding values
of the placebo
group (P 0.001). Because
both groups
exhibited significant
weight loss (Table
2), we tested the
hypothesis that the
decrease in HbA1c in the
Caiapo group was
related to the changes
in body weight by
using ANOVA with body
weight as a covariate.
The P value was 0.041,
indicating
that a possible
influence of the change
in
body weight on the
improvement of
HbA1c cannot be
excluded. Accordingly,
body weight and HbA1c
changes correlated
significantly (r 0.618;
P
0.0002).
Fasting, OGTT, and
postprandial
glucose
Fasting blood glucose
(Table 2, Fig. 1)
decreased at 2 months in
both groups
(Caiapo group: P 0.001;
placebo
group: P 0.05), but the
decrease was
greater in the Caiapo
group (P 0.0289
versus the placebo
group). No further
decrease
was observed in the
placebo group
afterward, where fasting
glucose levels in
the Caiapo group
continued to decrease
(at 3 months: P 0.001
versus the placebo
group). The frequency of
achieving
mean fasting blood
glucose levels below
the upper normal limit
(126 mg/dl) after 3
months of treatment was
evaluated: there
were 48.3% responders in
the Caiapo
group versus 7.7% in the
placebo group
(P 0.0005, 2 test).
Figure 2 shows the
differences between
the Caiapo and placebo
groups in
regard to glucose values
measured 2 h after
oral administration of
glucose (Table
2). No significant
changes from baseline
were observed in the
placebo group at 2
and 3 months. In the
Caiapo group, a
progressive
decrease occurred (P
0.005 at
1 and 2 months; P 0.001
at 3 months
versus the placebo
group). Within the
Caiapo
group, the differences
from baseline
were statistically
significant at any data
point (P 0.001).
Blood glucose levels
measured 2 h after
lunch decreased
significantly in the
Caiapo group after 2 and
3months (Table
2). In the placebo
group, a nonsignificant
decrease was observed
until 2 months
(P 0.14), but there was
no further
change after that time.
Blood glucose levels
measured 2 h after
dinner at baseline
were more elevated in
the Caiapo group
than in the placebo
group (P 0.05, Table
2). They became
virtually identical
after
2 and 3 months; however,
when
evaluating the
progressive decrease in
blood glucose levels
versus baseline, we
observed a statistical
significance within
the Caiapo group after 2
and 3 months,
whereas in the placebo
group, the difference
compared with baseline
was significant
only at 3 months.
Body weight, blood
pressure, and
lipid levels
Body weight was similar
at baseline (P
0.8) and decreased
significantly in both
groups at 3 months, but
the decrease was
more pronounced in the
Caiapo group
(Table 2). In fact,
despite similar body
weight at 3 months (P
0.67), the difference
versus baseline was
higher in the Caiapo
group (3.7 0.3 vs. 1.0
0.3 kg,
P 0.0004). Overall, 26
subjects in the
Caiapo group and 18
subjects in the placebo
group lost weight during
the study.
Blood pressure did not
change; at the end
of the study, the mean
blood pressure was
136.2 2.0/81.6 1.2 mmHg
in the
Caiapo group and 137.2
2.1/81.7
1.0 in the placebo group
(P 0.15 versus
baseline, Table 1). Mean
cholesterol at
baseline was similar in
the two groups
(P 0.276); at 3 months,
it was significantly
higher, as at baseline,
in the placebo
group, whereas it was
slightly
decreased in the Caiapo
group, without
reaching statistical
significance (P
0.08). At the end of the
treatment period,
cholesterol levels in
the Caiapo group
were lower than those in
the placebo
group (P 0.05). There
were no significant
differences in
triglyceride levels
neither
between nor within the
groups; P
values ranged from 0.2
to 0.8.
Tolerability and safety
At the end of the study,
the patients expressed
their opinions about
gastrointestinal
tolerability (poor,
acceptable, good,
excellent). Tolerability
was very good in
the Caiapo group, in
which only three
subjects reported a
negative opinion.
Similarly, no negative
opinions were expressed
by the subjects in the
placebo
group (P 0.8181 Caiapo
versus placebo).
Regarding adverse
events, 16 were
reported in the Caiapo
group and 14 were
reported in the placebo
group. In six subjects
in the Caiapo group and
two subjects
in the placebo group, a
relation with the
medication could not be
excluded. These
adverse events were
mainly of
gastrointestinal
nature (constipation,
gastric pain,
meteorism) and of mild
intensity.
CONCLUSIONS— In this
study, we
confirmed the beneficial
effects of Caiapo
on glucose and serum
cholesterol levels in
type 2 diabetic patients
treated by diet
(16) after 3 months of
administration.
This effect was observed
in improved fasting
blood glucose levels as
well as improved
glucose levels during an
OGTT
and in the postprandial
state. In addition,
we demonstrated for the
first time an
improvement
in long-term glucose
control
as expressed by the
significant decrease in
HbA1c.
The glucose-lowering
potency of Caiapo
has long been
recognized, and over
the past decades, it has
been commercialized in
Japan as an antidiabetic
medication.
However, publications on
the
efficacy and safety of
this compound consisted
mainly of case reports
and uncontrolled
studies. We have
recently
performed a pilot study
in 18 type 2 diabetic
patients over a period
of 6 weeks and
reported a significant
decrease in plasma
glucose levels (16). The
duration of the
study, however, was too
short to allow an
evaluation of long-term
parameters of
glucose control, such as
HbA1c. Therefore,
the present study was
designed to
address this issue and
to further extend
the knowledge about the
safety of Caiapo.
Regarding glucose
control, the data of the
pilot study were
confirmed, and Caiapo
can be regarded as an
effective compound
in the treatment of type
2 diabetes. After 3
months of treatment,
48.3% of patients in
the Caiapo group had
fasting blood glucose
levels 126 mg/dl, which
is diagnostic
for diabetes.
HbA1c was lowered by
0.5%, and
thus, the
glucose-lowering potency
of Caiapo
is in the range or even
beyond that of
compounds such as
acarbose (17) or
nateglinide (18).
Furthermore, baseline
glucose control was
fairly good, as
indicated
by an HbA1c of 7–7.2%,
and one
could speculate whether
Caiapo would
have proven more
efficient if patients
with
higher HbA1c levels had
been studied.
The improvement of
glucose control
comprised fasting as
well as postprandial
blood glucose levels and
raises a question
regarding of the mode of
action of Caiapo.
In a previous study, we
investigated
the effect of Caiapo by
performing oral
and intravenous glucose
tolerance tests in
type 2 diabetic patients
(19). The study
showed an improvement in
insulin sensitivity
as the responsible
mechanism for
the amelioration of
glucose tolerance,
while any effect on
glucose absorption or
insulin secretion was
excluded. These
findings were in
accordance with a study
in obese Zucker fatty
rats (14), in which
glucose tolerance
increased in response to
100 mg/kg of Caiapo
powder per day. The
effects, demonstrated by
an enhanced
[14C]glucose uptake in
isolated adipocytes,
were comparable to
treatment with
50 mg/kg of troglitazone
per day in a pairfed
group. Contrary to
troglitazone, no
weight gain could be
seen after Caiapo
treatment in those
animals. Whereas the
active substance
responsible for the
glucose-
lowering effect in this
extract of
white-skinned potatoes
is not entirely
known, an acidic
glycoprotein has been
identified as possible
candidate (15) and
is currently under
thorough investigation.
Unlike in animals and in
our pilot
study, we observed a
decrease in body
weight in both groups;
however, this decrease
was more pronounced in
the Caiapo
group. After further
analyzing the
HbA1c data by using body
weight change
as a covariate, a
possible influence of
weight loss on the
improvement in glucose
control was shown for
the Caiapo
group. We cannot,
however, quantify the
exact contribution of
weight loss on the
effects observed. In
both groups, the
decrease
in body weight may be
due partly
to a change in lifestyle
under the conditions
of a controlled study.
However, reduction
of body weight was
definitely
more sustained in the
Caiapo group, and
this raises a question
about a possible
mechanism of Caiapo in
decreasing body
weight. This issue,
however, remains unclear
and requires further
investigation.
At this stage,
malabsorption can be
excluded
by analysis of safety
laboratory parameters.
Because the tolerability
of
Caiapo was considered
very good, with
only three subjects
reporting a negative
opinion, a potential
gastrointestinal side
effect is unlikely to be
responsible for the
reduction of body
weight. From the time
course of weight loss
and improvement of
glucose control,
however, we hypothesize
that the continuing
decrease in glucose at
a stable body weight
during the last
month supports an
intrinsic action of
Caiapo
beyond weight loss,
presumably by
means of those effects
seen in previous
studies,
e.g., by increasing
insulin sensitivity.
Finally, we found in
this, as well as in
the pilot study (16), a
beneficial effect of
Caiapo on serum
cholesterol levels.
Although
we have not determined
LDL or
HDL cholesterol levels
in the present
investigation,
the pilot study showed
that
this effect was confined
only to LDL cholesterol.
Because the improvement
in insulin
sensitivity exerted by
Caiapo is not
expected to alter
cholesterol levels, a
second
compound, which is not
yet identified,
could be responsible for
this effect.
Weight loss in these
patients could also
contribute to the
lowering of cholesterol
levels; however, the
amount of this reduction
exceeds the extent
expected from a
weight loss of 3.7 kg.
No change in the
main safety parameters
(blood pressure
and other laboratory
measurements) was
observed with Caiapo,
and the tolerability
was considered good, as
also indicated by
the very low number of
adverse events.
These were similar
between the respective
groups, with only a
slightly higher number
of mild gastric problems
during administration
of Caiapo.
In conclusion, this
study confirms the
beneficial effects of
Caiapo on fasting and
postprandial plasma
glucose levels, as
well as cholesterol, in
patients with type 2
diabetes. For the first
time, we demonstrated
the long-term efficacy
of Caiapo
on glucose control by
the observed reduction
of HbA1c. Thus, the
neutraceutical
Caiapo seems to be a
useful agent in the
management of type 2
diabetes.
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