J Ginseng Res 42 (2018) 90e97

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Journal of Ginseng Research
journal homepage: http://www.ginsengres.org

Research article

Efﬁcacy and safety of Panax ginseng berry extract on glycemic control:
A 12-wk randomized, double-blind, and placebo-controlled clinicaltrial
Han Seok Choi 1, Sunmi Kim 2, Min Jung Kim 3, Myung-Sunny Kim 3, Juewon Kim 2,
Chan-Woong Park 2, Daebang Seo 2, Song Seok Shin 2, Sang Woo Oh 4, *1

Division of Endocrinology and Metabolism, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Gyeonggi, Republic of Korea
Research and Development Center, Amorepaciﬁc Corporation, Yongin, Gyeonggi, Republic of Korea
Nutrition and Metabolism Research Group, Korea Food Research Institute, Seongnam, Gyeonggi-do, Republic of Korea
4
Department of Family Medicine, Dongguk University Ilsan Hospital, Goyang, Gyeonggi, Republic of Korea
2
3

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 23 March 2016
Received in Revised form
18 December 2016
Accepted 4 January 2017
Available online 10 January 2017

Background: Antihyperglycemic effects of Panax ginseng berry have never been explored in humans. The
aims of this study were to assess the efﬁcacy and safety of a 12-wk treatment with ginseng berry extract
in participants with a fasting glucose level between 100 mg/dL and 140 mg/dL.
Methods: This study was a 12-wk, randomized, double-blind, placebo-controlled clinical trial. A total of
72 participants were randomly allocated to two groups of either ginseng berry extract or placebo, and 63
participants completed the study. The parameters related to glucose metabolism were assessed.
Results: Although the present study failed to show signiﬁcant antihyperglycemic effects of ginseng berry
extract on the parameters related to blood glucose and lipid metabolism in the total study population, it
demonstrated that ginseng berry extract could signiﬁcantly decrease serum concentration of fasting
glucose by 3.7% (p ¼ 0.035), postprandial glucose at 60 min during 75 g oral glucose tolerance test by
10.7% (p ¼ 0.006), and the area under the curve for glucose by 7.7% (p ¼ 0.024) in those with fasting
glucose level of 110 mg/dL or higher, while the placebo group did not exhibit a statistically signiﬁcantdecrease. Safety proﬁles were not different between the two groups.
Conclusion: The present study suggests that ginseng berry extract has the potential to improve glucose
metabolism in human, especially in those with fasting glucose level of 110 mg/dL or higher. For a moremeaningful beneﬁt, further research in people with higher blood glucose levels is required.
Ó 2017 The Korean Society of Ginseng, Published by Elsevier Korea LLC. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords:
antihyperglycemic effects
clinical trial
glucose metabolism
oral glucose tolerance test
Panax ginseng berry

1. Introduction
Diabetes mellitus is a serious metabolic disorder characterized
by hyperglycemia and various life-threatening complications.
Despite enormous preventive efforts, diabetes mellitus is one of thefastest growing chronic disorders across the world. In 2010, an
estimated 285 million people worldwide suffered from diabetes
mellitus, and the number of people with diabetes mellitus is expected to rise to 439 million or 7.7% of the global adult population
aged 20e79 yr by 2030 [1]. According to the Korean National Healthand Nutrition Examination Survey conducted in 2013, the prevalence of diabetes mellitus in Korea for adults over age 30 yr was
estimated to be 11.0% [2].

Although no cure is yet available for diabetes mellitus, various
pharmacologic agents have been developed and are being used toenable blood glucose control. However, the current pharmaceuticals for diabetes mellitus have a number of limitations, such as
having adverse effects and high rates of failure in long-term glycemic control. This has led to research for alternative or complementary approaches, such as natural products or botanicals, whichhave some degree of efﬁcacy and mostly are without the troublesome side effects associated with the conventional pharmacologic
treatments. Furthermore, earlier intervention for glycemic control
is being emphasized for prevention or delay of diabetes mellitus in
the management of patients with prediabetes [3]. In this context,
alternative approaches using natural products may provide* Corresponding author. Department of Family Medicine, Dongguk University Ilsan Hospital, 27, Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10326, Republic ofKorea.
E-mail address: osw6021@gmail.com (S.W. Oh).
http://dx.doi.org/10.1016/j.jgr.2017.01.003
p1226-8453 e2093-4947/$ e see front matter Ó 2017 The Korean Society of Ginseng, Published by Elsevier Korea LLC. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

H.S. Choi et al / P. ginseng extract and glycemic control

additional strategies for the early management of diabetes mellitus
or prediabetes.
Ginseng is a slow-growing perennial herb that has been used asa traditional medicine for thousands of years in Asia. Ginseng has
been reported to have various pharmacological properties,
including anticancer, antiaging, anti-inﬂammatory, and antiallergy
effects [4e7]. Ginseng has also received attention from medical
researchers for its antihyperglycemic effects, which have been
demonstrated by in vitro [8,9] and in vivo animal studies [10e19]
and clinical trials [20e22]. Although both root and berry ofginseng were reported to possess antihyperglycemic effects, arecent in vivo study demonstrated that ginseng berry had morepotent antihyperglycemic effects than its root when used at thesame dosages [23]. Indeed, the ginseng berry has a distinct ginsenoside proﬁle and contains signiﬁcantly more ginsenosides than its
root [23,24]. For this reason, the ginseng berry may exert morepotent antihyperglycemic effects than its root. However, the antihyperglycemic effects of Panax ginseng berry have never been
explored in humans. Therefore, the objective of the present study
was to test the efﬁcacy and safety of a 12-wk treatment withginseng berry in participants with fasting glucose level between
100 mg/dL and 140 mg/dL, using a randomized, double-blind,placebo-controlled study design.
2. Materials and methods
2.1. Preparation of ginseng berry extract and HPLC analysis
Ginseng berry and placebo capsules were provided by Amorepaciﬁc Corporation (Gyeonggi, Korea). Freshly harvested 4-yr-old
Korean ginseng berries (P. ginseng Meyer) cultivated in Chungbuk
province of South Korea were used. The seeds were separated, andthe pulp and juice dried in hot air. The dried ginseng berries were
reﬂuxed with 70% ethanol for 10 h. The extract was ﬁltered andevaporated under vacuum at 45 C to obtain standardized Korean
ginseng berry extract. The concentration of seven major ginsenosides in ginseng berry extract was analyzed by HPLC (Fig. 1) [25].
Total ginsenoside concentrations (% w/w) were 19.99%. Individual
ginsenoside concentrations were 0.77%, 1.90%, 2.11%, 1.65%, 11.06%,
1.66%, and 0.84% for the ginsenosides Rb1, Rb2, Rc, Rd, Re, Rg1, andRg2, respectively. The content of ginsenoside Re in standardized
ginseng berry extract was maintained at 10%. Each 500-mg ginseng
berry capsule contained 250 mg of standardized ginseng berry
extract. The total treatment dose of ginseng berry extract was 1 g/d.
Placebo capsules were identical in appearance and ﬂavor to the91

ginseng berry capsules. During the trials, four capsules (2 capsules
at a single time before breakfast and dinner) of ginseng berry
extract or placebo were given daily for 12 wk.
2.2. Participants
The study participants were recruited from January 2014 toDecember 2014 in Dongguk University Ilsan Hospital (Koyang,
Gyeonggi, Korea) via hospital and subway advertisement. After thescreening test, participants with fasting blood glucose within arange of 100e140 mg/dL, whose age was between 20 yr and 75 yr,
were enrolled in this study. Exclusion criteria included: lipid
metabolism disorders; acute or chronic inﬂammatory disease;corticosteroid use within 4 wk of the study; acute cardiovasculardisease such as heart failure, myocardial infarction, or stroke; anallergy or hypersensitivity to any of the ingredients in the test
products; a history of disease that could interfere with the test
products or impede their absorption, such as gastrointestinal diseases or gastrointestinal surgery; participation in other clinical
trials within the previous 2 mo; renal disease such as acute/chronic
renal failure or nephrotic syndrome; abnormal hepatic liver function; use of antipsychosis drug therapy within 2 mo of the study; ahistory of alcohol or substance abuse; pregnancy or breast feeding;and laboratory test results, medical, or psychological conditions
that the researchers considered unsuitable for this study. In addition, participants taking glucose-lowering medications or insulin
injections were excluded from this study. This study was carriedout in accordance with the Declaration of Helsinki and wasapproved by the Institutional Review Board of Dongguk University
Ilsan Hospital (IRB No. 2013-81). A total of 72 participants wereenrolled in this study and provided their written informed consent
for the study after they were provided with a detailed description of
the experimental procedures and informed that they could withdraw from the study at any time.
2.3. Study design
This study was designed as a single-center, randomized, doubleblind, placebo-controlled clinical trial that lasted for 12 wk.
Following the screening visit, at which inclusion and exclusion
criteria were assessed, participants were randomly assigned toreceive ginseng berry extract or placebo using a computerized
method of random list generation. All participants, investigators,
pharmacists and study personnel were blinded to treatment allocation. The enrolled participants were scheduled to visit threeFig. 1. HPLC of ginseng berry extract. AU, absorbance units.

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J Ginseng Res 2018;42:90e97

times (at 0 wk, 6 wk, and 12 wk) during the trial and their clinicalinformation and trial data were collected during individual interviews conducted by a well-trained interviewer. All participants
underwent a thorough medical history review and a physical examination. Height and weight were obtained using standardized
techniques and equipment. Height was measured to the nearest
0.1 cm and weight was measured to the nearest 0.1 kg. The bodymass index (BMI) was calculated as body weight in kg divided by
the square of height in m (kg/m2). Participants were questioned
about their daily food intake by the 24-h recall method and physicalactivity during the past 7 d. Compliance with study restriction andcapsule consumption was monitored by means of daily documentation by participants on individualized study calendars and countof returned capsules on the second and third visit. During theintervention period, participants were prohibited from glucocorticoid treatments, glucose-lowering medications or insulin injections, thyroid medications, and any medication or functional
food that the researchers considered unsuitable.
2.4. Measurements of efﬁcacy
The primary efﬁcacy measure was changes of fasting andpostprandial glucose concentration during the 75 g oral glucose
tolerance test (OGTT) before and after intervention. The secondary efﬁcacy measures were changes of fasting and postprandial
insulin, triglyceride, high-density lipoprotein cholesterol, lowdensity lipoprotein cholesterol, and total cholesterol levels. At
0 wk and 12 wk, a 75 g OGTT was performed after an overnight
fast (fasting for at least 8 h). Venous blood samples were thencollected at 0 min, 60 min, and 120 min for measurements ofserum glucose and insulin levels. Also, fasting blood samples
were collected at each visit to measure the lipid proﬁle. Tubes
were centrifuged at 2000 g to isolate plasma or serum, andstored at e70 C until analysis. Blood samples were analyzed on a
Cobas c702 analyzer (Roche Diagnostics, Basel, Switzerland).
Serum glucose concentrations were measured using the hexokinase method with a Cobas c702 analyzer (Roche Diagnostics).
Serum insulin concentrations were measured by the electrochemiluminescence immunoassay using a Cobas c602 analyzer(Roche Diagnostics). The homeostasis model assessment of insulin resistance (HOMA-IR) and b cell function (HOMA-b cell) were
calculated using the following equations:
HOMA-IR ¼ [fasting plasma insulin (mIU/mL)  fasting plasma
glucose (mM)]/22.5,(1)
HOMA-b cell ¼ [20  fasting plasma insulin (mIU/mL)]/[fasting
plasma glucose (mM) e 3.5].
(2)
Hemoglobin A1c (HbA1c) was measured by an G8 glycohemoglobin analyzer (Tosoh Corporation, Tokyo, Japan) using the
HPLC method. Fasting serum concentrations of triglyceride andtotal cholesterol were measured using the enzymatic colorimetricmethod with a Cobas c702 analyzer (Roche Diagnostics). Highdensity lipoprotein and low-density lipoprotein cholesterol were
measured by the homogeneous enzymatic colorimetric methodwith a Cobas c702 analyzer (Roche Diagnostics).
2.5. Assessment of safety
Safety was assessed by adverse events reported by participants,
physical examination, and laboratory parameters. During the trial,
all participants were asked to report potential adverse events. Vital
sign of each participant including systolic and diastolic bloodpressure and pulse rate was measured at every visit. Systolic anddiastolic blood pressure was measured using the left arm of theseated patient with an automatic blood pressure monitor after
resting for > 5 min. Pulse rate per min was determined by counting
the number of beats on the participant’s wrist for 15 s and multiplying this number by 4 to yield beats/min. Laboratory parameters
including complete blood count, alkaline phosphatase, aspartatetransaminase, alanine aminotransferase, total protein, albumin,blood urea nitrogen, and creatinine were measured at 0 wk and 12
wk as part of a safety assessment.
2.6. Statistical analyses
Differences in mean change from baseline between the treatment groups were examined using the linear mixed model for
repeated measures data unless otherwise speciﬁed. A paired t test
was used to determine signiﬁcance of change from baseline withineach treatment group. The demographic and baseline characteristics of each treatment group were compared by the independent t
test for the continuous variables or c2-test for the categorical data.
All p values shown are two-tailed. A p value < 0.05 was consideredsigniﬁcant. Calculations and statistical analyses were performed
using SPSS (version 18.0.0; SPSS Inc., Chicago, IL, USA). All the data
were represented as mean  standard deviation.
2.7. Analyzing metabolomics proﬁling from serum and dataprocessing
The metabolomics proﬁling from serum of study participants
were analyzed. UPLC coupled to quadrupole time-of-ﬂight (QTOF)eMS analysis was performed using an Acquity UPLC system(Waters, Miliford, MA, USA). The column was an ACQUITY UPLC
BEH C18 column (2.1 mm  100 mm, 1.7mm, Waters) at a ﬂow rateof 0.35 mL/min. The mobile Phase A was water with 0.1% formic
acid, and mobile phase B was acetonitrile with 0.1% formic acid. The
gradient conditions were 0.5% B rising to 70% in 8 min to a
maximum 90% after 8 min and then the equilibrated at 0.5% B for
2 min. The Q-TOF-MS was operated in positive and negative electrospray ionization mode within a mass range of 50e1,000 m/z. The
operating parameters were as follows: cone voltage, 30 V; acapillary voltage, 3.0 kV; source temperature, 150 C; desolvation
gas temperature, 300 C. The raw data were processed using Progenesis QI data analysis software (Nonlinear Dynamic, Newcastle,UK) for chromatographic alignment, normalization, peak picking,and compound identiﬁcation. The resulting data sets were imported into SIMCA-P version 12.0.1 (Umetrics, Umeå, Sweden) for
multivariate analysis and were mean-centered scaled.
3. Results
3.1. Baseline characteristics of the study participants
A total of 72 participants were initially randomized in this study.
Among these participants, nine participants dropped out. Amongthe nine dropouts, six participants withdrew consent because ofadverse events or personal reasons, and three participants were
excluded because of poor compliance. Thus, a total of 63 participants (29 in the ginseng berry group and 34 in the placebo group)
who had completed the 12-wk treatment without major protocol
violations and had a compliance rate of over 70% were analyzed for
efﬁcacy. All participants who entered the study and received atleast one dose of the study medication were assessed for safety anddemographics (Fig. 2). As shown in Table 1, there was no signiﬁcantdifference between the two groups in baseline demographic characteristics including sex, age, BMI, blood pressure, pulse rates,
alcohol consumption, and smoking.

H.S. Choi et al / P. ginseng extract and glycemic control

93

Fig. 2. Randomization scheme and participant disposition. AE, adverse event; SAE, serious adverse event.

3.2. Efﬁcacy
For both groups, within- and between-treatment differences inparameters of glucose or lipid metabolism were assessed (Table 2).
There was no difference in serum concentration of glucose andinsulin from the 75 g OGTT and HbA1c measures before and after
the intervention. No difference for these parameters was foundbetween the two groups. Also, there was no signiﬁcant difference inthe lipid proﬁle for within- and between-treatment differencesamong participants in this study. In subgroup analyses in thosewith fasting glucose level of 110 mg/dL or higher (Fig. 3), however,serum concentration of fasting glucose signiﬁcantly decreased by
3.7% (from a baseline of 120.25  10.32 mg/dL to an endpoint valueof 115.81  9.30 mg/dL, p ¼ 0.035) and that of postprandial glucose
at 60 min during the 75 g OGTT also signiﬁcantly decreased by

10.7% (from 231.75  37.58 ng/dL to 206.94  40.28 mg/dL,
p ¼ 0.006) in the ginseng berry group after intervention, while theplacebo group did not exhibit such a statistically signiﬁcantdecrease. Total glucose area under the curve (AUC) of the ginseng
berry group improved by 7.7% (23,090.63  4,273.52 mg*min/dL to
21,307.50  4,298.89 mg*min/dL, p ¼ 0.024). There was a signiﬁcant difference in between-treatment in 75 g OGTT indices of
postprandial glucose level at 60 min (p ¼ 0.017) and total glucose
AUC (p ¼ 0.040). However, there was no signiﬁcant difference forwithin- and between-treatment in other parameters of glucose
metabolism including HbA1c and insulin levels. When we conducted subgroup analyses by sex, we found that ginseng berry
extract treatment in men induced a signiﬁcant decrease of postprandial glucose level at 60 min (from a baseline of 213  52.71 mg/
dL to an end point value of 193  44.89 mg/dL) during 75 g OGTT

Table 1Baseline demographic characteristics of the study participantsSex (M/F)
Age (y)Height (cm)Weight (kg)BMI (kg/m2)
SBP (mmHg)
DBP (mmHg)
Pulse (beats/min)
Alcohol

SmokingNo
Yes
Amount of alcohol
consumption (units3)/wk)No
Yes
Number of cigarettes/dGinseng berry group (n ¼ 34)

Placebo group (n ¼ 38)

Total(n ¼ 72)

p1)

18 / 1652.76  10.24
164.62  9.23
69.57  12.22
25.52  2.87
128.85  13.75
82.38  12.32
73.91  12.08
19 (55.88)
15 (44.12)
14.55  19.13

24/ 1451.89  9.46
165.79  8.63
70.89  13.04
25.61  3.05
128.55  14.56
81.16  11.27
73.76  8.64
13 (34.21)
25 (65.79)
12.46  9.64

42 / 30
52.31  9.78
165.24  8.88
70.27  12.59
25.57  2.95
128.69  14.08
81.74  11.71
73.83  10.33
32 (44.44)
40 (55.56)
13.26  13.86

0.3802)
0.709
0.580
0.660
0.908
0.929
0.661
0.953
0.0652)27 (79.41)
7 (20.59)
19.29  7.32

27 (71.05)
11 (28.95)
15.90  11.55

54 (75.00)
18 (25.00)
17.29  9.90

0.4142)

Values are presented as mean  standard deviation or n (%)
BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure
1)
Analyzed by independent t test except sex (M/F), alcohol (No/Yes), and smoking (No/Yes)
2)
Analyzed by Chi-square test
3)
1 unit ¼ 10 g of pure alcohol

0.700

0.506

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J Ginseng Res 2018;42:90e97

Table 2
Changes in serum glucose and insulin during 75 g OGTT, HbA1c, and lipid proﬁle before and after intervention
Ginseng berry group (n ¼ 29)

Glu 0 min (mg/dL)
Glu 60 min (mg/dL)
Glu 120 min (mg/dL)
AUC-G (mg*min/dL)
Ins 0 min (mU/mL)
Ins 60 min (mU/mL)
Ins 120 min (mU/mL)
AUC-I (mU*min/mL)
HbA1c (%)
HOMA-IR
HOMA-b cell
Total cholesterol (mg/dL)
Triglyceride (mg/dL)þ
LDL-cholesterol (mg/dL)
HDL-cholesterol (mg/dL)

p2)

Placebo group (n ¼ 34)

Baseline

12 wk

p1)

Baseline

12 wk

p1)

112.31  12.39
211.07  45.46
174.03  57.89
21,254.48  4,490.98
7.07  4.01
46.28  21.68
48.29  23.28
4,437.76  1,864.94
5.85  0.38
2.01  1.24
51.58  27.21
190.07  31.49
157.55  115.56
122.07  33.01
54.28  14.34

112.03  10.14
200.17  44.11
173.48  57.97
20,575.86  4,386.08
7.10  4.38
47.09  26.11
49.08  27.44
4,510.68  2,330.82
5.89  0.41
1.97  1.24
52.94  31.57
191.62  32.57
158.29  148.05
117.48  32.64
55.97  18.14

0.864
0.085
0.940
0.188
0.962
0.864
0.877
0.854
0.554
0.857
0.779
0.770
0.833
0.355
0.319

112.88  11.06
215.56  45.91
171.44  48.23
21,463.24  4,157.40
7.06  4.04
48.66  25.08
55.28  27.56
4,789.61  2,258.30
5.81  0.37
2.00  1.24
51.65  29.37
197.88  30.80
151.62  76.33
131.15  32.19
53.24  13.68

112.79  12.13
213.71  45.46
170.76  50.51
21,329.12  4,271.74
7.72  5.37
52.86  28.75
56.58  30.05
5,100.60  2,502.90
5.81  0.47
2.16  1.54
58.34  40.10
203.59  30.52
150.82  83.46
133.94  29.88
57.71  18.31

0.957
0.740
0.920
0.783
0.476
0.417
0.716
0.424
0.897
0.542
0.345
0.060
0.945
0.315
0.002**

0.935
0.276
0.990
0.439
0.591
0.630
0.932
0.668
0.675
0.559
0.547
0.476
0.814
0.176
0.190

Values are presented as mean  standard deviation
AUC-G, area under the curve for glucose; AUG-I, area under the curve for insulin; Glu, glucose; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HOMA-IR, homeostasis
model assessment-insulin resistance; HOMA-b cell, homeostasis model assessment-b cell function; Ins, insulin; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test
1)
For within-treatment differences analyzed by paired t test
2)
For between-treatment differences analyzed by linear mixed model for repeated measures data

after intervention (p ¼ 0.020), while placebo treatment in men did
not show any effect on the same parameter. There was also a signiﬁcant between-treatment difference in postprandial glucose
level at 60 min (p ¼ 0.046). However, there was no within- andbetween-treatment difference in women.
3.3. Safety
There were no signiﬁcant differences in number and type ofreported adverse events for the two groups (Table 3). Only ﬁve
adverse events were reported in the ginseng berry group, while 11
adverse events occurred in the placebo group. There was one
serious adverse event reported in the placebo group and no cases in
the ginseng berry group. In demographic proﬁles and vital signs,
there were no differences in within- and between-treatmentgroups except for a signiﬁcant decrease in diastolic blood pressure from a baseline of 79.93  10.97 mmHg to an end point valueof 73.93  11.45 mmHg in the ginseng berry group (p ¼ 0.010).
When within- and between-treatment differences in safety laboratory parameters were assessed, there was a within-treatment
difference in hematocrit (p ¼ 0.047) and lymphocyte count(p ¼ 0.034) in the ginseng berry group and a between-treatment
difference in red blood cell count between the two groups(p ¼ 0.042). However, these differences did not have clinicalsigniﬁcance.
3.4. Metabolomic proﬁling of serum of the study participants
For the metabolomic proﬁling of the participants (who weregrouped into 2 as the ginseng berry group and the placebo group),
blood samples were collected at the beginning (baseline) and 12 wk
after the start of experiment, and the samples were subjected to
UPLC/Q-TOF-MS. The metabolomics analysis identiﬁed 53 metabolites, listed in Table S1. Also variable importance of projection (VIP)
scores of the metabolites corresponding to ginseng berry consumption are presented. The intensity of the identiﬁed 53 metabolites in human blood samples is shown in Table S2. There were no
signiﬁcant differences between the ginseng berry group and theplacebo group during the 12 wk of treatment. No signiﬁcant differences in intensity of metabolites were observed in the placebogroup prior to the trial and after the 12-wk treatment (p > 0.05).
However, as the pre- and post-treatment blood samples in theginseng berry group were compared, a signiﬁcant decrease in thelevels of the following metabolites was observed: valine(p ¼ 0.027), leucine/isoleucine (p ¼ 0.011), glutamine (p ¼ 0.004),
methionine (p ¼ 0.017), xanthine (p ¼ 0.005), and phenylpyruvic

Fig. 3. Changes in serum glucose during 75 g oral glucose tolerance test before and after 12-wk intervention in subgroups with fasting glucose level of 110 mg/dL or higher. Values
are presented as mean  standard deviation. *p < 0.05 serum concentration of fasting glucose after 12-wk intervention. **p < 0.01 serum concentration of postprandial glucose at
60 min after 12-wk intervention. ***p < 0.05 serum concentration of postprandial glucose at 60 min in ginseng berry group compared with placebo group.

H.S. Choi et al / P. ginseng extract and glycemic control
Table 3Adverse events

Overview of AEs
1 AEs1 serious AEs
AE leading to discontinuation
Common AEs1) ( 5%)
Common cold
Urticaria
Other AEs
Gastric soreness
Epigastric pain
Cystitis
Periorbital edema
Herpes zoster
Rheumatoid knee pain
Rheumatoid trigger thumb
Sprain of lumbar spine
Severe cervical dysplasia
Urolithiasis
Tinea pedis
Serious AEs
Demyelinating disease

Ginseng berrygroup (n ¼ 34)

Placebo group(n ¼ 38)

5 (14.71)
02 (5.88)

11 (28.95)
1 (2.63)
2 (5.26)

1 (2.94)02 (5.26)
2 (5.26)

1 (2.94)
1 (2.94)
1 (2.94)
0
0
0
0
0
0
1 (2.94%)0000
1 (2.94)
1 (2.94)
1 (2.94)
1 (2.94)
1 (2.94)
1 (2.94)0
1 (2.94)0

1 (2.94)

Values are presented as n (%)
AEs, adverse events
1)
AEs with frequency  5% in any groupacid (p ¼ 0.012). At the same time, there was a signiﬁcant increasein levels of glycerophosphocholine (p ¼ 0.012), linoleoyl carnitine(p ¼ 0.015), lysophosphatidylethanolamine (18:2; p ¼ 0.011), andlysophosphatidylcholine (20:2; p ¼ 0.053). Pearson’s correlation
analysis was also conducted to assess the relationship between
phenotypic and metabolomic changes. As shown in Fig. S1 and S2,
signiﬁcant metabolomic changes in the ginseng berry group closely
correlated with several phenotypic changes. Brieﬂy, changes infasting blood glucose level positively correlated with levels of
xanthine (r ¼ 0.531, p ¼ 0.003), alanine (r ¼ 0.430, p ¼ 0.018), succinic acid (r ¼ 0.668, p < 0.001), phenylalanine (r ¼ 0.450,
p ¼ 0.013), creatine (r ¼ 0.385, p ¼ 0.036), and leucine/isoleucine(r ¼ 0.432, p ¼ 0.017; Fig. S1). The postprandial blood glucose at the
60-min level showed a signiﬁcant positive correlation with levels of
alanine (r ¼ 0.559, p ¼ 0.001), succinic acid (r ¼ 0.458, p ¼ 0.012),
creatine (r ¼ 0.427, p ¼ 0.019), lysophosphatidylcholine (20:5;
r ¼ 0.535, p ¼ 0.002), and lysophosphatidylcholine (22:6; r ¼ 0.471,
p ¼ 0.009) and negatively correlated with level of corticosterone(r ¼ 0.499, p ¼ 0.005) (Fig. S2). Based on these results, metabolomic
changes for each participant in the ginseng berry group wereclearly observed, although the overall changes in the ginseng berrygroup were not signiﬁcantly different from those in the placebogroup.
4. Discussion
Ginseng consists of several parts including root, leaf, and berry.
Generally, ginseng root has been widely used as traditional medicine for thousands of yr in Asia. Compared to the ginseng root, theberry portion of ginseng has not been commonly used for medical
purposes. Meanwhile, the major active components of ginseng arereported to be ginsenosides, a class of natural product steroid
glycosides and triterpene saponins [26]. Although > 30 ginsenosides have been isolated from various parts of ginseng including
root and berry, the most common ginsenosides based on HPLC
analysis include Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1 [27]. While theginseng root has long been the favored source of these active ingredients, recent studies have shown that the ginseng berry contains higher levels of ginsenoside content and with a distinct

95

ginsenoside proﬁle compared with the ginseng root [23,24]. The
ginsenoside Re in particular was four- to six-times higher in the
berry than in the root of ginseng [24]. For this reason, each part ofthe plant may exhibit different pharmacological activities. Since the1980s, the number of published studies exploring the effects ofginseng on glucose metabolism has remarkably increased. This
includes reports demonstrating the therapeutic efﬁcacy andmechanism of antihyperglycemic activity of ginseng root extracts in
multiple in vitro [8,9] and in vivo studies using various diabetic
animal models [10e19]. More recent studies have shown that not
only root but also berry of ginseng has a potent antihyperglycemic
activity [14,15]. Furthermore, Dey et al [23] compared the antihyperglycemic activity between ginseng root and berry in C57BL/6J
ob/ob mice and concluded that ginseng berry is more potent thanginseng root in terms of glucose reduction when used at the same
dosage. It was demonstrated that administration of ginsenoside Re,a major constituent of ginseng berry, signiﬁcantly improved
glucose tolerance without affecting body weight in C57BL/6J ob/ob
mice [14,28], which suggests that ginsenoside Re plays a crucial
pharmacological role in glucose metabolism.
Several clinical trials investigating the effects of ginseng on
diabetes-related parameters in human volunteers have been published, although the results from these studies have varied
considerably [20e22,29e33]. Until recently, most clinical studies
with ginseng have been conducted with its root. As far as we know,
the present study is the ﬁrst clinical trial to investigate the antihyperglycemic activity of ginseng berry in human volunteers. In
this study, although we could not ﬁnd signiﬁcant differences
within- and between-treatment for glucose and lipid metabolism
in the total number of participants, we observed signiﬁcant improvements in serum concentration of fasting and postprandial
glucose at 60 min during 75 g OGTT in those with fasting glucose
level of 110 mg/dL or higher, which implies that ginseng berry
extract may be more beneﬁcial to people with higher glucose levels.
At present, the mechanisms underlying ginseng’s antidiabetic
activity are not fully understood. A growing number of evidence
from in vitro and in vivo studies suggest that the antihyperglycemic
actions of ginseng are complex and attributable to various mechanisms including regulation of insulin secretion or sensitivity,
modulation of gastrointestinal absorption, and regulation of inﬂammatory pathway [34]. A recent animal study showed thattreatment with ginseng berry extract signiﬁcantly increased insulin
secretion in b-cell-deﬁcient diabetic mice induced by streptozotocin [35]. In this study, the proliferation of b-cells by ginseng berry
extract was also demonstrated in vitro. Another animal study using
aged C57BL/6 mice showed that ginseng berry extract feeding
signiﬁcantly decreased HOMA-IR and fasting insulin levels, andameliorated pancreatic islet hypertrophy, which suggests that the
improvement of insulin sensitivity might contribute to a decrease
in insulin demand [36]. In the same study, it was also demonstrated
that ginseng berry extract could activate insulin receptor substrate1 and protein kinase B, the important molecules in the insulin
signaling pathway. In our study, we showed that ginseng berrytreatment induced metabolomic changes, some of which wereassociated with blood glucose level. This ﬁnding suggests thatmetabolomic changes by ginseng berry treatment might beinvolved in its antihyperglycemic activity, although we needfurther investigation to give a detailed account for it.
In the present study, there was no difference of HbA1c levels
between control and ginseng berry group at the end of the study.
We speculate that the lack of improvement in HbA1c levels byginseng berry might be due to the participants’ well-controlled
glucose status when they were enrolled in the study. The baselinemean value of HbA1c was 5.83% at the beginning of the study andmost of our participants had a prediabetic condition rather than a96

J Ginseng Res 2018;42:90e97

diabetes mellitus one. Nevertheless, we found a signiﬁcant
improvement in postprandial glucose levels at 60 min during OGTTin those with fasting glucose levels of 110 mg/dL or higher. Recently,
the importance of postprandial hyperglycemia has been highlighted [37], as uncontrolled postprandial hyperglycemia can increase glucose variability. It was suggested that ﬂuctuating glucose
produces oxidative stress, thereby inducing endothelial dysfunction and inﬂammation, both well-known risk factors for cardiovascular disease [38]. The relationship between postprandial
hyperglycemia and the risk of cardiovascular event was identiﬁedin type 2 diabetes [39]. Furthermore, it was shown that treating
postprandial hyperglycemia by acarbose may reduce the incidenceof cardiovascular disease in people with impaired glucose tolerance
or type 2 diabetes [40,41].
The limitations of the present study include the following. First,
most participants enrolled in the present study were prediabetic.
Only a small number of participants were diagnosed with type 2
diabetes. Therefore, caution should be used when we generalize
these results to people with type 2 diabetes. In addition, withhaving only slightly higher than normal levels of fasting glucose in
the total population of this study made it difﬁcult to ﬁnd a significant improvement in parameters related to glucose metabolism.
Second, the lack of follow-up data in the dropouts precluded
intention-to-treat analyses in order to strengthen the interpretation of the data.
In summary, the present study was the ﬁrst randomized,
double-blind, placebo-controlled clinical trial to examine the efﬁcacy and safety of P. ginseng berry extract on glycemic control inhuman volunteers. Although the present study failed to show signiﬁcant antihyperglycemic effects of ginseng berry extract on parameters related to glucose and lipid metabolism in the total study
population, it demonstrated that compared with placebo, ginseng
berry extract can signiﬁcantly improve the fasting and postprandial
glucose levels over 12 wk in those with fasting glucose levels of
110 mg/dL or higher. This study also showed that there was nosafety concern with the long-term consumption of ginseng berry
extract. In conclusion, the results of our study suggest that ginseng
berry extract has the potential to improve glucose metabolism inhumans, particularly those with fasting glucose levels of 110 mg/dL
or higher, and without safety concerns. Further research in people
with higher glucose levels is required.
Conﬂicts of interest
The authors declare no conﬂicts of interest.
Acknowledgments
This work was supported by the Research and Development(R&D) program of MOTIE/KIAT (Establishment of Infra Structure for
Anti-aging Industry Support, #N0000697), the Convergence ofConventional Medicine and Traditional Korean Medicine R&D
Program funded by the Ministry of Health and Welfare through the
Korea Health Industry Development Institute (HI14C0558), andAmorepaciﬁc.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jgr.2017.01.003.
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