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Diabetes-Ameliorating Effects of Fermented Red Ginseng and Causal Effects on
Hormonal Interactions: Testing the Hypothesis by Multiple Group Path Analysis
Article in Journal of Medicinal Food · May 2013
DOI: 10.1089/jmf.2012.2583 · Source: PubMed

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JOURNAL OF MEDICINAL FOOD
J Med Food 16 (5) 2013, 383–395# Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2012.2583

FULL COMMUNICATIONS

Diabetes-Ameliorating Effects of Fermented Red Ginseng and Causal Effects on
Hormonal Interactions: Testing the Hypothesis by Multiple Group Path Analysis
Kwang Jo Lee,1 Sook Yeon Lee,2 and Geun Eog Ji1,3
1

Department of Food and Nutrition, Research of Institute of Human Ecology,
Seoul National University, Seoul, Korea.
2
College of Pharmacy, Sahmyook University, Seoul, Korea.
3
Research Institute, Bifido Inc., Hongcheon, Gangwon, Korea.

ABSTRACT Although diagnostic criteria for metabolic syndrome (MtS) vary among various health professionals andorganizations, blood glucose dysregulation and insulin resistance are common to all definitions. Red ginseng is beneficial for
glucose regulation and insulin sensitivity but the mechanism is not yet elucidated. Ginsenosides Rh1 and Rg3 act as ligands ofthe estrogen receptor, and Rh2 and compound K act as ligands of the glucocorticoid receptors, which may influence thediabetes markers. The objective of this study was to test the hypothesis that there are significant causal relationships among
diabetes-related markers and several hormones, and assess whether or not the consumption of fermented red ginseng (FRG)
influences these causal relationships by multiple group path analysis and conventional statistical analyses. The 93 postmenopausal women were randomly divided into two groups for a double-blind trial. FRG powder and placebo were provided
for 2 weeks. The data were analyzed by multiple group path analysis and the mean between groups were compared. The
model’s goodness of fit was excellent, with a root mean square error of approximation of 0.00, and comparative fit index of
1.00. The FRG group exhibited significantly increased levels of dehydroepiandrosterone sulfate (DHEAS), growth hormone(GH), and estradiol (E2), and they exhibited decreased levels of glycosylated hemoglobin (HbA1c), insulin, and homeostatic
model assessment of insulin resistance. With regard to the hypothesis, the blood glucose lowering effects of FRG were due tothe negative effects of aldosterone and increased GH, which was associated with DHEAS and E2. Even though the differencesof variables between both groups were small, the total effects of these variables may indicate beneficial changes for theprevention of diabetes in healthy postmenopausal women.
KEY WORDS:  blood glucose  compound K  DHEAS  estradiol  ginsenoside  HOMA-IR  insulin resistance  pathmodel  Rg3

Studies have reported that the incidences of MtS in
postmenopausal women were as high as 35.1% in Latin
America,3 35% in Portugal,4 33% in the United States,5 and27.3% in China.6 A low level of E2 is considered as a major
cause of MtS, and estrogen hormone replacement therapy(HRT) decreases this risk in postmenopausal women. For
example, postmenopausal women who undergo HRT show a
12.9% decrease in insulin resistance and a 35.8% reductionin the incidence of diabetes.7 However, a study by the
Women’s Health Initiative reported that HRT increases therisk of gynecological cancer and obesity and has a negligible
beneficial effect on cardiovascular diseases.8 Given the severity of these HRT side effects, the study of estrogen
mimics—including selective estrogen receptor modulators—
has emerged as an important MtS treatment area.9 On theother hand, many studies have shown that the rate of onset of
MtS is related not only to estrogen levels, but also to thelevels of other hormones,10 which may be due to the broadand complicated interrelationships of the constituents of theendocrine system.

INTRODUCTIONT

he World Health Organization defines metabolic
syndrome (MtS) as ‘‘glucose intolerance, impaired
glucose tolerance or diabetes mellitus, and/or insulin resistance together with two or more of the following: elevated arterial pressure, elevated plasma triglycerides,
central adiposity, microalbuminuria, and several othercomponents (e.g., hyperuricemia, coagulation disorders,raised PAI-1, etc.).’’1
Although these diagnostic criteria include a broad spectrumof definitions and points of emphasis,2 several major components of MtS diagnosis are shared among various professional bodies, especially, blood glucose and insulin resistance.
Article received 18 September, 2012. Revision accepted 24 February, 2013.
Address correspondence to: Geun Eog Ji, PhD, Department of Food and Nutrition,
Research of Institute of Human Ecology, Seoul National University, 56-1 Sillim-dong,Gwanak-gu, Seoul 151-742, Korea, E-mail: geji@snu.ac.kr or Sook Yeon Lee, PhD,
College of Pharmacy, Sahmyook University, Hwarangro-815 nowon-gu, Seoul
139-742, Korea, E-mail: leesy45@syu.ac.kr

383

384

LEE ET AL.

Ginseng is one of the most popular herbal supplements in
Asia, especially Korea, China, and Japan, and records document its use back to 2000 years.11 In modern times, thepopularity of ginseng has grown in western countries as well.
For example, ginseng ranked as one of the top-10 sellingherbal supplements in the United States in 2003.12 The primary pharmacological components in ginseng are known as
ginsenosides, chemicals that have a steroid skeleton. Studies
have shown that ginsenosides, Rh1 and Rg3 act as ligands ofthe estrogen receptor (ER), and that Rh2 and compound K(CK) act as ligands of the glucocorticoid receptor (GR).13,14
Many studies have reported that red ginseng is beneficial for
glucose regulation and insulin sensitivity.15,16 One possible
hypothesis would be that ginsenosides can influence thevariables of diabetes, and the functioning of the endocrine
system. The first objective of this study was to test the hypothesis that there are significant causal relationships among
diabetes-related markers and several hormones by a pathanalysis. The second objective was to test the hypothesis that
consumption of fermented red ginseng (FRG) influences
these causal relationships by multiple group path analysis andconventional statistical analyses.

117 Participants
Double blind random trial

58 PlaceboBaseline (1st)Sample collection

59 FRG

2 weeks

44 Placebo

49 FRGIntervention (2nd)Sample collection

Sample measure

Data Analysis

FIG. 1. Flowchart of this study.

Statistical analyses
MATERIALS AND METHODS
Participants and study design
This study was approved by the Institutional Review
Board of Sahmyook University (Seoul, Korea). Women
aged 50–73 years were recruited from several Catholic
churches (Seoul, Korea). Participants with hypertension ordiabetes and those taking prescription or other drugs were
excluded. Dietary supplements were not allowed during theexperimental period.
The 117 volunteers were randomly divided into two
double-blinded groups. FRG powder was provided by Bifido
Inc. (Gangwon-do, Korea). One group (the FRG group) took
FRG capsules three times a day, each time taking a dose of
three capsules (2.1 g/day) for 2 weeks. The other group
took a placebo containing starch. The composition of the
FRG capsules was crude saponin, 258.6 mg/g; CompoundK, 57.05 mg/g; Rg3, 53.85 mg/g; Rh2, 11.97 mg/g; Rg2,
5.72 mg/g; Rh1, 2.99 mg/g; and Rb1, 0.023 mg/g. Blood
samples, after 8 hours of fasting, were collected before andafter the 2-week intake of either the FRG or the placebo
capsules. The blood samples were collected between 8:00 a.m.
and 10:00 a.m. Urine samples were collected 24 hours prior
to collection of blood samples. All 117 women participatedin the first blood sample collection, but only 93 womenparticipated in the second blood sample collection (Fig. 1).
Ninety of the 93 participants were postmenopausal, andthree were perimenopausal.
Forty subjects were selected from both groups (20 subjects per group) after matching age, height, weight, and BMI
and were further analyzed for several hormones (Table 1).
All biochemical components were measured by the Green
Cross Reference Lab (Gyeonggi-do, Korea). The analyticalmethods are shown in Appendix Table A1.

Given that the production of the estrogen hormone slowly
decreases during the first five postmenopausal years, thethree perimenopausal women were included in this analysis.
The baseline comparisons of both groups between the firstbaseline sample and the second postintervention values
were compared by independent t-test. The means of thepostintervention samples were also compared between the
FRG group and the placebo group, with an analysis of covariance (ANCOVA) by SPSS 18.0 (SPSS, Inc., Chicago,
IL, USA). The level of statistical significance was P < .05
and a statistical tendency was considered as P < .1. The
outliers that were over three times the standard deviation
were excluded in the estrogen, insulin, and homeostasis
model of insulin resistance (HOMA-IR) variables. The
HOMA-IR index was calculated as follows:
HOMA-IR index ¼ ½fasting serum glucose ðmMÞ· fasting serum insulin ðlU=mLÞ=22:5:
The unmeasured hormones of 53 participants, and somedata that could not be measured due to the detection limitation of the instruments, were considered as random missing
values. Following this, 10 data sets were generated using themultiple imputation method and then were analyzed by
Mplus 6.11 (Muthén & Muthén, Los Angeles, CA, USA).
RESULTS
Anthropometric data
Table 2 shows the anthropometric variables of the participants. There was no significant difference between the
FRG and the placebo groups in the mean values of age,weight, height, BMI, waist, and hip circumsference.

385

DIABETES-AMELIORATING EFFECTS OF FERMENTED RED GINSENG
Table 1. Comparison of Hormone and Diabetes Markers
Between Fermented Red Ginseng Group and Placebo Group
MarkerDiabetes
Glucose (mg/dL)
HbA1c (%)
HOMA-IR
Insulin (lU/mL)
HPA axis
ACTH (pg/mL)

Group (n)2nd sample D[2nd - 1st]
(mean)b(mean – SD)a

Placebo (44)
FRG (49)
Placebo (44)
FRG (49)
Placebo (43)
FRG (48)
Placebo (43)
FRG (48)

89.6 – 6.8
87.4 – 7.1
5.8 – 0.3**
5.7 – 0.3**
1.4 – 0.8*
1.4 – 0.7*
6.4 – 3.6**
6.2 – 2.9**

Placebo (44) 20.4 – 10.1
FRG (49)
22.7 – 11.8
ADH (pg/dL)
Placebo (20)
0.8 – 0.2
FRG (20)
0.8 – 0.2
CBG (ng/mL)
Placebo (20) 6178 – 8294
FRG (20)6293 – 8469
Cortisol (lg/dL)
Placebo (44) 11.2 – 3.5
FRG (49)
10.8 – 3.8
Free cortisol (lg/day) Placebo (41) 22.5 – 15.8
FRG (47)
19.8 – 14.0
CRH (ng/mL)
Placebo (20)
0.2 – 0.1
FRG (20)
0.5 – 1.0
HPG axis
E2 (pg/mL)
Placebo (19) 14.5 – 7.3*
FRG (19)18.3 – 7.3*
FSH (mIU/mL)
Placebo (20) 74.0 – 24.3
FRG (20)68.0 – 18.5
LH (mIU/mL)
Placebo (20) 38.8 – 14.8
FRG (20)30.3 – 9.0
HPS axis
Aldosterone (ng/dL)
Placebo (20)
6.2 – 3.5
FRG (20)
8.4 – 3.6
DHEAS (lg/dL)
Placebo (44) 65.2 – 31.4*
FRG (49)
66.2 – 29.1*
GH (ng/mL)
Placebo (20)
0.9 – 1.2
FRG (20)
1.8 – 1.4
IGF-1 (ng/mL)
Placebo (20) 144 – 49
FRG (20)
144 – 67

2.2
2.5
0.1
0.1
0.2**
- 0.1**
1.0**- 0.2**
2.3
0.9
- 0.1
0.0
2269
2114
- 0.2
0.9
- 5.5
- 2.1
0.0
0.2
- 7.4*
1.0*
0.1
2.4
1.0
- 0.3
0.2
0.9
- 6.2**
0.5**
- 0.4
- 0.1
- 2.3
1.8

Data expressed as a mean SD.
Values are significantly different as indicated (*P < .1, **P < .05,***P < .01) by aanalysis of covariance or bindependent t-test.
ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CBG,
cortisol-binding globulin; CRH, corticotropin-releasing hormone; DHEAS,
dehydroepiandrosterone sulfate; E2, estradiol; FRG, fermented red ginseng;
FSH, follicle stimulating hormone; GH, growth hormone; HbA1c, glycosylated hemoglobin; HOMA-IR, homeostasis model of insulin resistance; HPA
axis, hypothalamic–pituitary–adrenal axis; HPG axis, hypothalamic–pituitary–
gonadal axis; HPS axis, hypothalamic–pituitary–somatotroph axis; IGF-1,
insulin-like growth factor-1; LH, luteinizing hormone.

Mean
Table 1 shows the means of the variables from the intervention samples taken after 2 weeks, and the difference
between the first baseline sample and the week 2 intervention sample. The results from the week 2 intervention
sample show that the level of growth hormone (GH, 1.8 vs.
0.9 ng/mL), estradiol (E2, 18.3 vs. 14.5 pg/mL), and dehy-

Table 2. Anthropometric Data of ParticipantsAge (years)
Weight (kg)Height (cm)BMI (kg/m2)
Waist circumference (cm)Hip circumference (cm)
Waist/hip ratio

Control(placebo; n = 44)

FRG group(n = 49)

58.4 – 5.9
57.6 – 6.6
156.5 – 5.3
23.6 – 2.5
33.4 – 2.3
37.4 – 2.0
0.9 – 0.0

58.4 – 5.5
57.1 – 6.7
157.7 – 5.3
22.9 – 2.4
32.8 – 2.4
37.0 – 1.9
0.9 – 0.0

Data are mean – SD values.
BMI, body mass index.

droepiandrosteronesulphate (DHEAS, 66.2 vs. 65.2 lg/dL)
were significantly higher in the FRG group than in theplacebo group, at P < .1. The mean values of insulin (6.2 vs.
6.4 lU/mL), HbA1c (5.70 vs. 5.77%), and the HOMA-IR(1.36 vs. 1.42) indexes were significantly lower in the FRG
group than in the placebo group.
When the first and second sample were compared,
the values of E2 (1.0 vs. - 7.4 pg/mL) and DHEAS (0.6 vs.
- 6.2 lg/dL) were higher in the FRG group than in theplacebo group, and the values of insulin ( - 0.2 vs. 1.0 lU/mL),
glycosylated hemoglobin (HbA1c, 0.06 vs. 0.09%), and
HOMA-IR ( - 0.09 vs. 0.17) were significantly lower in the
FRG group than in the placebo group, but the values of GH
were not significantly different (Table 1).
Path model
In this model, all paths were established based on the results of precedents, which can be found in previously published studies, but these paths were not based on a strict
statistical correlation.17 The studies that established the precedents for these path models are presented in Table 3,1,18–33
and the correlations are presented in Appendix Table A2.
Path analysis is a useful statistical analysis method, one that
can analyze several causal relationships among several variables at the same time. Further, multiple group path analysis
allows for the comparison of the path coefficients between two
groups, followed by identifying statistical significances ofthe differences between two path coefficients. Therefore, themultiple group path analysis may be a useful tool for the
analysis of the complicated interrelationship between hormonal and diabetes variables. One of the major purposes of thismultiple group path model was to analyze whether there wasinvariance of path coefficients across two groups. The testingof equivalence was conducted in two steps. First, a baselinemodel was established, followed by equality constraints ofthe path coefficients of the two groups. The path coefficients ofthe baseline model are presented in Table 4, and the final pathmodel after equality constraints test presented in Figure 2.
An unstandardized path coefficient shows that when acausative variable increases by a value of one unit, the resultant variable changes in value. In the baseline model(Table 4), when E2 increased by 1 pg/mL, GH increased to0.160 ng/mL in the FRG group; whereas GH decreased to0.301 ng/mL (P = .02) in the placebo group. To compare the386

LEE ET AL.
Table 3. Description of Paths in Present Study

PathContents

Reference

ACTH/aldosterone

When ACTH is treated to rat, the level of 11beta-hydroxylase, mRNA in the adrenal
gland and in the cerebral cortex is increased, and aldosterone synthease mRNA
increases in all central nerves except the cerebral cortex, and decreases in the adrenal
gland.

Ye et al.18

ACTH/cortisol
ACTH/DHEAS
ADH/ACTH
Aldosterone/glucose

ACTH was released after the administration of CRH and followed by the release of GCs.
When ACTH is treated, the DHEA in serum and brain is increased.
In a study of sheep, CRH and AVP stimulated the release of ACTH.
When aldosterone is given to mice, the level of blood glucose is increased. Whenaldosterone is administered to liver cells, the promoter activity of glucose6-phosphatase is increased.
In normal circulatory condition, 80–90% of cortisol strongly binds with CBG, 10–15% of
the cortisol binds with low affinity, and 5–10% is unbinding free form.
The gene of G6Pase has two glucocorticoid response elements. When glucocorticoid
is administrated to a liver cell in vivo, the activity of G6Pase is increased by 40%.
ACTH is released after the administration of CRH
When CRH is treated, the DHEA in serum and brain is increased.
The administration of DHEAS to rats increases the level of aldosterone.
When DHEAS is treated to rats, the level of cortisol shows a significant increase
When DHEAS is ingested by a human, the level of serum E2 and IGF-1 is increased.
When the level of estrogen increases during the menstrual cycle, the level of GH also
increases.
FSH receptor is expressed in follicle cells only, FSH is a decisive element for
estrogen production in the ovary. FSH induces aromatase activity in the granulose
cell of a hair follicle.
Administration of FSH suppresses the release of LH in the hypothalamus and isindependently mediated by ovary dose dependently.
When GH is treated, the mean level of blood glucose is increased.
The administration of growth hormone increases fasting blood glucose in patient deficientin growth hormone.
Glycated hemoglobin represents the mean value of blood
Insulin decreases the activity of G6Pase and the level of mRNA.
LH stimulates the production of estrogen in the ovary.

Kling et al.19
Torres and Ortega20
Matthews and Challis21
Yamashita et al.22

Cortisol/free cortisol
Free cortisol/glucose
CRH/ACTH
CRH/DHEAS
DHEAS/aldosterone
DHEAS/cortisol
DHEAS/E2
E2/GH
FSH/E2

FSH/LH
GH/Glucose
GH/HbA1c
Glucose/HbA1c
Insulin/glucose
LH/E2

several causative variables with the one resultant variable,
standardized path coefficients were used. When a causative
variable changed by one standard deviation, the resultant
variable changed by the same value of the standardized pathcoefficient. In the FRG group, when aldosterone increased to
one standard deviation (3.6 ng/dL), blood glucose significantly decreased to 0.147 of one standard deviation (7.1 mg/
dL · 0.147 = 1.00 mg/dL), whereas free cortisol increased to
one standard deviation (14.0 lg/day), and blood glucose increased to 0.032 of one standard deviation of blood glucose(7.1 mg/dL · 0.032 = 0.227 mg/dL) (Table 4).
To assess whether or not the difference in a path between
groups was significant, the Wald test with cross-group equality
constraints was employed. When the difference between theoriginal chi-square value and the cross-group equality constrained chi-square value was higher than 3.84, the hypothesisof cross-group equality was rejected, which meant the differences were statistically significant. In the path of aldosterone to blood glucose, when the path coefficients between the
FRG group and the placebo group were constrained for cross-

Lewis et al.23
Lin et al.24
Kling et al.19
Torres et al.20
Song et al.25
Song et al.25
Jankowski et al.26
Ovesen et al.27
Fogle et al.28

Gordon et al.29
Qian et al.30
Woodmansee et al.31
Alberti and Zimmet1
Argaud et al.32
Macklon et al.33

group equality, the value of the Wald test was 6.90 and the
P value was 0.009. Therefore, the path coefficients between
both groups were significantly different. (Table 4).
Based on the results listed above, the final model was
made and presented in Figure 2. The model’s goodness of fit
was excellent, as accounted for by the measures root meansquare error of approximation (0.00) and comparative fit
index (1.00). The chi-square of the model was 146.5; thedegree of freedom value was 198.
DISCUSSION
Hormones
The highest percentages of ginsenosides in this FRG capsule were Rg3 and compound K, which are the ligands of ER
and GR, respectively. Therefore, the hormones evaluated inthis study were those on the hypothalamic–pituitary–adrenal(HPA) axis and those on the hypothalamic–pituitary–gonadal(HPG) axis; the central variables for diabetes were blood
glucose, HbA1c, insulin, and HOMA-IR.

387

DIABETES-AMELIORATING EFFECTS OF FERMENTED RED GINSENG
Table 4. Path Coefficients of the Baseline Model and Values of the Wald Test
Path
ACTH / aldosterone
PlaceboFRG
ACTH / cortisol
PlaceboFRG
ACTH / DHEAS
PlaceboFRG
ADH / ACTH
Placebo
FRG
Aldosterone / glucose
Placebo
FRG
Cortisol / free cortisol
Placebo
FRG
Cortisol / glucose
Placebo
FRG
Free cortisol / glucose
PlaceboFRG
CRH / ACTH
PlaceboFRG
CRH / DHEAS
PlaceboFRG
DHEAS / aldosterone
PlaceboFRG
DHEAS / cortisol
Placebo
FRG

Unstandardized
estimate

Standardized
estimate- 0.3 – 0.1**- 0.1 – 0.2- 0.4 – 0.2***- 0.1 – 0.2

0.4 – 0.1***
0.4 – 0.1***

0.5 – 0.1***
0.5 – 0.1***

0.0 – 0.1
0.1 – 0.1

0.0 – 0.2
0.2 – 0.1

0.0 – 0.4
0.1 – 0.3

0.0 – 0.3
0.1 – 0.2

Wald
testa v2D
0.51
0.03
0.69
0.06
6.90***

0.9 – 0.3***
0.0 – 0.3

0.6 – 0.1***- 0.1 – 0.3

0.4 – 0.2**
0.1 – 0.1

0.3 – 0.1**
0.1 – 0.1

2.30
1.05
- 0.1 – 0.2
0.1 – 0.2

- 0.1 – 0.1
0.1 – 0.2

0.2 – 0.1*
0.0 – 0.2

0.2 – 0.1*
0.0 – 0.2

0.1 – 0.7
0.3 – 0.5

0.1 – 0.3
0.2 – 0.3

0.4 – 0.3
0.3 – 0.2*

0.2 – 0.2
0.3 – 0.2*

0.1 – 0.2
0.3 – 0.2

0.1 – 0.2
0.2 – 0.2

- 0.1 – 0.1
0.1 – 0.2

0.0 – 0.1
0.0 – 0.1

0.56
0.04
0.05
0.16

Path
DHEAS / estradiol
Placebo
FRG
Estradiol / GH
PlaceboFRG
FSH / estradiol
PlaceboFRG
FSH / LH
Placebo
FRG
GH / glucose
Placebo
FRG
GH / HbA1c
Placebo
FRG
Glucose / HbA1c
Placebo
FRG
Glucose / HOMA
Placebo
FRG
Insulin / glucose
Placebo
FRG
Insulin / HOMA
PlaceboFRG
LH / estradiol
Placebo
FRG

Unstandardized
estimate

Standardized
estimate

0.2 – 0.2
0.4 – 0.3

0.1 – 0.2
0.3 – 0.2

0.2 – 0.3
- 0.3 – 0.1**- 0.4 – 0.2**
0.2 – 0.3

- 0.1 – 0.3- 0.5 – 0.2**- 0.2 – 0.3- 0.5 – 0.2**

0.4 – 0.2*
0.4 – 0.2*

0.4 – 0.2**
0.5 – 0.2*

Wald
testa v2D
0.33
2.42
1.28
0.00
0.60

- 0.5 – 0.4- 0.2 – 0.3- 0.3 – 0.2- 0.2 – 0.2- 0.4 – 0.3
0.7 – 0.2***- 0.2 – 0.24
0.6 – 0.1***

0.6 – 0.2***
0.5 – 0.1***

0.5 – 0.1***
0.5 – 0.1***

0.2 – 0.0***
0.2 – 0.0***

0.2 – 0.0***
0.2 – 0.0***

0.3 – 0.2*
0.2 – 0.2

0.3 – 0.2*
0.2 – 0.2

0.9 – 0.0***
0.9 – 0.0***

0.9 – 0.0***
1.0 – 0.0***

7.81***
0.09
0.75
0.10
2.26
0.30
0.2 – 0.2
- 0.1 – 0.5

0.2 – 0.2
- 0.1 – 0.3

0.19

Data expressed as a mean – SD. Values presented in boldface indicate significant difference (P < .05) between FRG and control groups by the Wald test.
aWald test was performed using one unstandardized path coefficient.
Values are significantly different (*P < .1, **P < .05, ***P < .01) by analysis of covariance.

The peak period of DHEAS production is between theages of 20–30 years, followed by a decrease of 2% every
year, until the rate of release is finally only 10–20% of thepeak levels at 70 years of age.34 Studies reported that
DHEAS, E2, and GH have serial causative relationships.
Pluchino and colleagues reported that when DHEAS was
administered to postmenopausal women, the level of estrogen
increased,35 which is consistent with the path coefficient of
DHEAS to E2 (0.307) in the equality constraint state (Fig. 2).
When the level of estrogen increases during the menstrual
cycle, the level of GH also increases,27 which is consistent
with the path coefficient of E2 to GH (0.160) in the FRG
group, but not consistent with the path coefficient of E2 to GH
in the placebo group ( - 0.301; Table 4). Studies have reported that the level of GH is negatively correlated with theincidence of insulin resistance. Colao et al. reported that afteradministration of GH, subjects showed a significant decrease

in insulin resistance,36 which is consistent with the path coefficient of GH to blood glucose ( - 0.358) in this study. Nam
et al. reported that there was no difference in the levels of GH
between a red ginseng group and a placebo group, whereas
red ginseng consumption with aerobic exercise was found to
significantly increase the level of GH,37 which is consistent
with the higher GH level in the FRG group. Salpeter andcolleagues reported in a meta-analysis that HRT decreases
insulin resistance (HOMA-IR) by 12.9%, and reduces the riskof diabetes by 35.8% in postmenopausal women.38 Considering the report of Salpeter et al.,38 in this study, the higher
level of E2 in the FRG group should be beneficial for glucose
management.
Since the levels of E2, GH, and DHEAS gradually decrease along with ageing and the postmenopausal period,
even though the mean differences between groups were
small, the cumulative effects of these hormonal increments

388

LEE ET AL.

CRH

LH

DHEAS

FSH

44

0.2

0.0

ACTH

0.378

0.299

ADH

97

0.054

Cortisol

Estradiol

GlucoseHOMA-0.2830.5

14

GH-0.354/0.697

0.916

0.154

1

22

-0.1310.695/-0.110

0.121

0.

Insul

2

Aldo

0.167

Free
Cortisol

20

0.105

18

0.140

0.433

-0.

0.2

-0.374

09

0.0

HbA1c

FIG. 2. The final path model of hormones and diabetes markers.
Two paths showed the significant differences in the present pathmodel. First, the path coefficient of aldosterone (Aldo) on blood
glucose was significantly different across two groups (P = .005).
Second, the path coefficient of growth hormone (GH) on blood glucose was significantly different across two groups (P = .009). These
invariance tests were conducted by the Wald test, and the numbers inparenthesis present the unstandardized path coefficients.

in the FRG group can be interpreted as having the potential
to affect the progress of diabetes.
Vuksan and colleagues reported that the consumption of
red ginseng improved glucose and insulin regulation in 19
participants with well-controlled type 2 diabetes. Red ginseng consumption decreased fasting plasma insulin by 8 pM,
plasma glucose during a 75 g oral glucose tolerance test
(OGTT) by 8–11%, and it increased the fasting-HOMAinsulin sensitive index by 33%.15 In this study, the insulinlevels and HOMA-IRs of the second sample, and the gap
between the second and first sample, were both significantly
lower in the FRG group than in the placebo group (Table 1).
Vogeser et al.39 reported that the distribution of HOMA-IR
results was mainly determined by fasting serum levels rather
than fasting glucose levels, because of the high variability offasting serum insulin concentrations. In this path model, thecontribution ratios in HOMA-IR of insulin and blood glucose were 0.918 and 0.157 respectively in the standardized
path coefficients (Table 4).

Clinically, the HbA1c level reflects the average concentration of blood glucose for 2 or 3 months. The American Diabetes Association considers HbA1c as a criterion for the
diagnosis of diabetes. Normally, HbA1c increases 0.1% every
decade after 40 years of age.40 In the difference between thesecond and first sample in this study, the level of HbA1c wassignificantly lower in the FRG group than in the placebo group.
In the path analysis, aldosterone was the largest single
factor in the decreased blood glucose of the FRG group.
Aldosterone regulates blood glucose through a mineral
corticoid receptor (MR)-dependent mechanism with GLUT4and GLUT2, and an MR-nondependent mechanism with aninsulin receptor.41 GLUT4 is a glucose transporter that is
highly expressed in skeletal muscle and adipose tissue.42
When insulin stimulates the cells, GLUT4 in the cytosol
translocates to the cell membranes, and transports glucose
across the cell membrane. Therefore, the impairment of
GLUT4 functionality is an important cause of insulin resistance, as seen in type 2 diabetes patients.43 When aldosterone
is administrated to rats, the level of GLUT4 protein drops
remarkably in muscle cells, whereas glucocorticoid treatments increase the expression of GLUT4.44 Since the effectsof aldosterone on GLUT4 are related to MR-MR homodimer
and MR-GR heterodimer, and it is well known that cortisol isa ligand of GRs, cortisol levels can also related to the GLUT4
mechanism. Huang et al. reported that when CK or Rg1 wasadministered to adipocyte cell lines, GLUT4 mRNA andglucose uptake increased. This increase implicated GLUT4
movement from intracellular vesicles to the plasma membrane.45 The MR-nondependent mechanism in glucose regulation of aldosterone is related to the gene expression of theinsulin receptor. GREs on the promoter of insulin receptor
are regulated by an MR-MR homodimer or an MR-GR heterodimer. When aldosterone was administered to MIN6 beta
cells, a pancreas cell line, insulin release was suppressed.46
Since the aldosterone and glucocorticoid share the GR and
MR,47 it is possible that ginsenosides, especially compound K,
may interact with aldosterone functions.
In conclusion, in the conventional average comparison,
the FRG group significantly increased the levels of DHEAS,
GH, and E2, and decreased the levels of HbA1c, insulin, and
HOMA-IR. In the hypothesis of this path model, DHEAS,
E2, GH, blood glucose, and HbA1c established a causal
relationship. The blood glucose lowering effects of the FRG
group came from two causal effects. One line was thenegative effects of aldosterone and the other line was GH,
which was connected with DHEAS and E2. Considering theparticipants were healthy postmenopausal women who may
be assumed to have a healthy level of homeostasis, the small
difference of several variables may be reasonable andsomewhat desirable, and the cumulated summation of thesevariable changes in the FRG group cannot be ignored as apotential preventive effect for postmenopausal women at
risk of developing diabetes.
The fermentation process of ginseng transforms the inactive state of the ginsenosides, Rb1, Rc, Rb2, Rb3, and Rd,
to a bioactive state, rendering the ginsenosides into an easily
absorbable structure such as CK.48 The effect of red ginseng

DIABETES-AMELIORATING EFFECTS OF FERMENTED RED GINSENG

can vary depending on the type, ratio, period, and ginsenoside dose. Therefore, for a better understanding of theeffects of ginseng, a study with a single type of ginsenosideand unhealthy participants, including those with diabetes or
cardiovascular disease, may prove instructive.

ACKNOWLEDGMENTS
We thank Mr. John Mensing (PhD Candidate, Departmentof Pali and Buddhist Studies, University of Peradeniya, Peradeniya, Sri Lanka), who assisted with the proofreading of thearticle. This work was supported by the Next-Generation
BioGreen 21 Program (No. PJ009543), Rural Development
Administration, and by the Small and Medium Business Administration (SA114187), Republic of Korea.
AUTHOR DISCLOSURE STATEMENT
No competing financial interests exist.
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(Appendix follows) /391

ACTH IRMA

Reagent
Kit name

Company,
nationality
Reference range

8–10 a.m.: 10–60
8–10 p.m.: 6–30

Packard, USA

Kit company,
Brahms, Germany
nationality
Analytical instrument
Instrument nameR-counter
Model nameCobra 5010 series
Quantum

E416
IRMA
Cold storage

Test code
Test method
Storage methodof sample

ACTH [pg/mL]

R-counterCobra 5010
seriesQuantum
Packard, USA
Supine:1.0–16.0
Standing:
4.0–31.0£ 4.7

Siemens, USA

Coat-A-Count
Aldosterone

E436
RIA
Cold storage

Aldosterone[ng/dL]

R-counterCobra 5010
seriesQuantum
Packard, USA

Vasopressin
1251
RIA kitDiaSorin, USA

E418
RIA
Cold storage

ADH (RIA)[pg/mL]a.m.: 5–25
p.m.: halfof a.m. values

R-counterCobra 5010
seriesQuantum
Packard, USA

Siemens, USA

Coat-A-Count
Cortisol

E435
RIA
Cold storage

Cortisol[lg/dL]

20–90

R-counterCobra 5010
seriesQuantum
Packard, USA

Siemens, USA

Coat-A-Count
Cortisol

E439
RIA
Cold storage

Cortisol, free[lg/dL]

Test name [units of measurement]

Molecular Devices, USAStandard
range inkit: 0.04–25

EIA reader
E max presion

Phoenix, USA

CRH EIA kit—
EIA
Cold storage

CRH [ng/dL]

Appendix Table A1. Reagents and Instruments in This Study

M: 80–560
F: 35–430

Packard, USA

R-counterCobra 5010 series
Quantum

Siemens, USA

Coat-A-CountDHEA-Sulfate

E431
RIA
Cold storage

DHEA-S [lg/dL]

M, adult: 40–115
M or F,
prepubertal: £ 40
F, follicular:
61–394
midcycle: 122–437
luteal: 156–350
postmenopausal:£ 40(continued)

Packard, USA

R-counterCobra 5010 series
Quantum

ICN, USA

Total Estrogen

E010
RIA
Cold storage

Estrogen(E1) [pg/mL]

392
Advia Centaur
Siemens, USA
M, 13–70 years:
1.4–18.1
F, follicular:
2.5–10.2
midcycle:
3.4–33.4
luteal: 1.5–9.1
pregnant: < 0.3
postmenopausal:
23.0–116.3

Advia Centaur
Bayer, USA

M: < 52F, follicular:
11–165
midcycle: 146–526
luteal: 33–196
postmenopausal:< 37

Advia Centaur

Advia Centaur
FSH
Siemens, USA

Cold storage

E421
CLIA

FSH [mU/mL]

70–110

Advia 1650
Bayer, Japan

Advia

GlucoseHexokinase
Bayer, USA

C123
Enzymatic
methodRefrigeration

Glucose (S)[mg/dL]

Immulite

DPC, USAIGF-1[ng/mL]

Cold storage

E455
CLIA

1–5 years: 49–327
6–8 years: 52–345
9–11 years: 74–551
12–13 years: 143–850
14–17 years: 193–996
18–25 years: 116–584
26–40 years: 109–329
41–55 years: 87–267> 55 years: 55–225

Immulite 2000
DPC, USA

Immulite 2000

DPC, USA

Immulite 2000 GH IGF-1

Cold storage

E417
CLIA

HGH (S)[ng/mL]

Variant II Turbo Immulite 2000
Bio-Rad,
DPC, USA
Germany
3.5–6.5
M, adult: £ 1.0
F, adult: £ 10.0

Variant

Variant II
HbA1c T.
Bio-Rad,Germany

Refrigeration

C431
HPLC

HbA1c
[%]

Advia Centaur FSH

Cold storage

E422
CLIA

LH
[mU/mL]2.6–24.9

M, 20–70 years:
1.5–9.3> 70 years:
3.1–34.6
F, follicular:
1.9–12.5
midcycle:
8.7–76.3
luteal: 0.5–16.9
pregnant: < 1.5
postmenopausal:
15.9–54.0

ModularAdvia Centaur
Analytics
E170
Advia Centaur
Roche, Germany Siemens, USA

Roche, Germany Siemens, USA

Insulin

Cold storage

E441
ECLIA

Insulin[lU/mL]

CLIA, chemiluminescence immunoassay; ECLIA, electrochemiluminescence immunoassay; EIA, enzyme immunoassay; HPLC, high-performance liquid chromatography; IRMA, immunoradiometric assay;
RIA, radioimmunoassay.

Model nameCompany,
nationality
Reference

Kit company,
nationality
Analytical instrument
Instrument name Centaur

Advia Centaur
Estradiol
Bayer, USA

Refrigeration

Storage methodof sample

Reagent
Kit name

C001
CLIA

Test code
Test method

Estrogen (E2)
[pg/mL]

Test nameAppendix Table A1. (Continued)

393

DHEAS
PearsoncoefficientSignificance(two tail)Sum ofsquareCovariancen

CRH
PearsoncoefficientSignificance(two tail)Sum ofsquareCovariancen- 543.483- 13.935
40- 3.661- 0.094
40

0.032
40

- 0.094
40

4.256
0.112
39

0.015

- 0.323- 0.009
39

0.959

0.407

0.011
39

0.155
1040.763
26.68640- 0.330**

0.037- 72.670- 1.863
40

0.119

0.255

3625.281

39.405
93

0.229

0.129

- 0.388**

0.008

0.248

13.43740- 0.072
40

0.678
39

25.750

0.251

0.188

0.015
39

0.567

1

0.112
39

4.256

524.054- 2.805

0.248
0.129

1

- 0.00939- 0.3230.015- 0.388**

0.011
39

0.407

0.959

0.008

CRH

0.497

- 0.111- 2.805

1.229- 3.661- 0.07240

0.497- 0.111

0.020

0.754

1

- 0.368**

Aldosterone- 0.051

ADH

0.754

- 0.051

Aldosterone
Pearson- 0.368**
coefficientSignificance
0.020(two tail)Sum of- 543.483
squareCovariance- 13.935n
40

ADH
PearsoncoefficientSignificance(two tail)Sum ofsquareCovariancen

ACTH
Pearson1
coefficientSignificance(two tail)Sum of
11,165.430
squareCovariance121.363n93ACTH901.2839382918.040

1

0.678
39

25.750

0.251

0.188

26.68640

1040.763

0.155

0.229

- 1.86340- 72.670

0.037- 0.330**

39.405933625.281

0.255

0.119

DHEAS

33.577401309.486

0.381

0.142

- 0.10639- 4.0440.477- 0.1177.317
40285.357

0.093

0.269

0.034
40

1.345

0.873

0.026

- 7.14640- 278.712

0.568- 0.093E2

157.30840

6135.009

0.154

0.230

- 0.124
39- 4.7310.775- 0.047- 1.31940- 51.440

0.919- 0.017- 0.58140- 22.663

0.350- 0.152- 67.696
40- 2640.150

0.057- 0.304

FSH

7.351
93

676.283

0.522

0.067

- 0.090
39- 3.405

0.195- 0.212- 1.99940- 77.965

0.326- 0.159

0.026
40

1.011

0.794

0.043

20.56793

1892.192

0.000

0.513***

GCs- 34.630
90- 3082.100

0.469- 0.077- 0.07836- 2.7380.838- 0.035- 9.14637- 329.270

0.404- 0.141- 0.072
37- 2.605

0.894- 0.023- 3.65490- 325.209

0.837- 0.022

fGCs- 2.12940- 83.025

0.764- 0.049

0.050
39

1.916

0.061

0.303

1.849
40

72.1270.019

0.369**- 0.00740- 0.2910.850- 0.031- 5.16840- 201.538

0.020- 0.366**

GH

38.604933551.608

0.080

0.183

0.104
39

3.944

0.418

0.133

5.382
40

209.888

0.153

0.230

- 0.08840- 3.446

0.632- 0.0783.841
93353.358

0.637

0.050

Glucose39.088933596.090

0.203

0.133

0.258
39

9.819

0.143

0.239

3.783
40

147.518

0.468

0.118

0.064
40

2.492

0.801

0.041

- 4.25793- 391.634

0.707- 0.040

HbA1c

343.82993

31,632.259

0.106

0.169

0.127
39

4.825

0.915

0.018

- 44.888
40- 1750.614

0.194- 0.210- 0.22840- 8.8880.893- 0.022

16.549931522.510

0.833

0.022

IGF1

0.024

- 0.357**

LH

8.861
90

788.628

0.241

0.125

0.051
38

1.884

0.318

0.166

1.427
39

54.235

0.352

0.153

0.022
39

0.818

0.772

0.048

3.662
90

(continued)

66.119402578.632

0.318

0.162

0.045
39

1.705

0.864

0.028

5.957
40

232.321

0.437

0.126

- 0.31440- 12.254

0.397- 0.138- 47.37640

325.886 - 1847.679

0.187

0.140

InsulinAppendix Table A2. Correlation Coefficients of Hormones in This Study—Two-Sided Test with Pearson Correlation Coefficients

394

GH
Pearson- 0.366**
coefficientSignificance
0.020(two tail)Sum of- 201.538
squareCovariance- 5.168n
40
0.019
72.127
1.849
40

0.850

- 0.291- 0.00740- 9.14637- 0.072370.369**- 329.270- 2.605- 0.031

0.404

0.050
39

1.916

0.061

0.303

- 0.07836- 2.7380.838- 0.035- 0.09039- 1.999
40

0.894

0.026
40

20.56793- 3.405- 77.965- 0.212- 0.124
39- 4.731

0.775

0.195

- 0.141

1.011

1892.192

33.57740- 0.10639- 2.12940- 83.025

0.764- 0.049- 34.630
90- 3082.100

0.469- 0.0777.351
93676.283

0.522

0.067

157.30840

6135.009

0.154

0.230

1309.486- 4.044- 0.047

0.381

0.142

DHEAS

0.477

- 0.117

CRH

0.326

- 0.023

0.794

0.000

- 1.31940- 0.58140- 0.159- 51.440- 22.663

0.043

0.919

7.317
40

0.034
40

0.350

285.357

1.345- 0.017

0.093

0.873

- 0.152

0.269

Aldosterone

0.026

ADH

0.513***

fGCs
Pearson- 0.022
coefficientSignificance
0.837(two tail)Sum of- 325.209
squareCovariance- 3.654n
90

GCs
PearsoncoefficientSignificance(two tail)Sum ofsquareCovariancen

FSH
Pearson- 0.304
coefficientSignificance
0.057(two tail)Sum of- 2640.150
squareCovariance- 67.696n
40

E2Pearson- 0.093
coefficientSignificance
0.568(two tail)Sum of- 278.712
squareCovariance- 7.146n
40

ACTH- 0.25240- 9.8240.879- 0.025- 22.26637- 801.559

0.311- 0.171- 4.51240- 175.953

0.273- 0.178- 51.292
40- 2000.403

0.044

2.205
40

85.990

0.646

0.075

128.509374626.337

0.018

0.387**

2.349
40

91.615

0.845

0.032

464.869
40

18,129.884

1- 51.292
40- 2000.403

0.044- 0.320**

FSH- 0.40240- 15.674

0.598- 0.0869.970
90887.288

0.091

0.179

13.235931217.652

1

2.349
40

91.615

0.845

0.032

- 4.51240- 175.953

0.273- 0.178

GCs

0.311

- 0.171

fGCs

2.172
37

78.186

0.604

0.088

228.452
90

20,332.205

1

9.970
90

887.288

0.091

0.179

128.509374626.337

0.018

0.387**- 22.26637- 801.559

Appendix Table A2. (Continued)- 0.320**55.11640

2149.515

1

E2

1.868
40

72.841

1

2.172
37

78.186

0.604

0.088

- 0.40240- 15.674

0.598- 0.0862.205
40

85.990

0.646

0.075

- 0.25240- 9.8240.879- 0.025

GH- 1.21340- 47.288

0.391- 0.13922.47690

2000.389

0.047

0.210**

2.282
93

209.940

0.396

0.089

3.729
40

145.429

0.868

0.027

8.702
40

339.385

0.256

0.184

Glucose2.160
40

84.225

0.265

0.181

- 4.97490- 442.690

0.754- 0.033- 5.18593- 477.044

0.163- 0.146- 42.26440- 1648.293

0.164- 0.2244.599
40

179.371

0.664

0.071

HbA1c

0.145

- 0.238

4.620
39

0.298

- 0.1714.904
87421.727

0.210

0.136

1.044
90

92.9570.252

16.20740- 0.59739

632.069 - 22.672

0.209

0.203

10.79390960.588

0.922

0.010

- 11.248
93- 1034.772

0.665

0.122

- 60.119 - 13.025
40
39- 0.0460.269- 0.179

LH(continued)

4.657
40

181.619

0.098

0.265

106.521373834.771

0.004

0.462***

3.932
40

153.336

0.583

0.089

171.17940

6675.971

0.000

0.618***- 17.07140

175.552 - 665.779

0.130

0.247

Insulin- 2344.634 - 494.963

0.770- 0.048

71.163402775.361

0.311

0.164

IGF1

395

View publication stats

3.783
40

0.064
40

0.048

0.772

0.818

0.022
39

0.140

0.187

325.886

3.662
90

0.864
1.705
0.045
39

0.437
232.3215.957
40

66.119402578.632

0.318

0.162

8.861
90

788.628

0.241

0.125

343.82993

31,632.259

0.106

0.169

39.088933596.090

0.203

0.133

38.604933551.608

0.080

0.183

DHEAS

- 5.18593- 42.264
40

1.044
90

- 13.02539

0.000
6675.971
171.17940- 665.779- 17.071
40

3.932
40

153.336

0.583

0.089

92.957- 494.963

0.618***

0.252

0.122

- 11.248
93- 1034.772

0.665

0.145

- 0.238- 60.11940- 2344.634

0.770- 0.046- 477.044- 1648.293- 0.0480.163- 0.1462.282
93209.940

0.396

0.089

GCs

0.164

- 0.2243.729
40

145.429

0.868

0.027

FSH

0.754

- 0.033

22.47690

2000.389

0.047

0.210**

fGCs

106.521373834.771

0.004

0.462***

4.904
87

421.727

0.210

0.136

10.79390960.588

0.922

0.010

- 4.97490- 442.690

Appendix Table A2. (Continued)

0.269- 0.1794.620
39

175.552

0.130

0.247

71.163402775.361

0.311

0.164

4.599
40

179.371

0.664

0.071

8.702
40

339.385

0.256

0.184

E2

Values are significantly different as indicated (**P < .05, ***P < .01) by analysis of covariance (SPSS v. 18).

0.028

0.051
38

1.884

0.318

0.166

0.127
39

4.825

0.915

0.018

0.258
39

9.819

0.143

0.239

0.104
39

3.944

0.418

0.133

CRH

0.126

1.427
39

54.235

0.352

0.153

- 44.88840- 8.8881522.510- 0.22840- 1750.614

0.893

0.833

16.54993

0.194- 0.0220.022- 0.210147.518

2.492

LH
Pearson- 0.357** - 0.138
coefficientSignificance
0.024
0.397
(two tail)Sum of- 1847.679- 12.254
squareCovariance- 47.376- 0.314n
40
40InsulinPearsoncoefficientSignificance(two tail)Sum ofsquareCovariancen

IGF1
PearsoncoefficientSignificance(two tail)Sum ofsquareCovariance
n

0.468

0.801

5.382
40

- 0.088
40

3.841
93
0.118

209.888- 3.446353.358

0.041

0.153

0.632

0.637

0.230

Aldosterone- 0.078

ADH

0.050

HbA1c
Pearson- 0.040
coefficientSignificance
0.707(two tail)Sum of- 391.634
squareCovariance- 4.257
n
93

GlucosePearsoncoefficientSignificance(two tail)Sum ofsquareCovariance
n

ACTH

4.657
40

181.619

0.098

0.265

- 0.59739- 22.672

0.298- 0.171

16.20740632.069

0.209

0.203

2.160
40

84.225

0.265

0.181

- 1.21340- 47.288

0.391- 0.139

GH

9.900
40

386.082

0.457

0.121

3.221
90

286.648

0.067

0.194

32.377932978.642

0.519

0.068

30.631932818.065

0.000

0.445***

49.534934557.118

1

Glucose- 2.14940- 83.798

0.907- 0.0192.678
90

238.352

0.266

0.119

50.169934615.574

0.471

0.076

95.597938794.933

130.631932818.065

0.000

0.445***

HbA1c- 0.46140

0.344- 0.156- 0.46140- 17.970

0.997- 0.001- 2.14940- 83.798

0.907- 0.0199.900
40386.082

0.457

0.121

LH

0.344

- 0.1565.532
90- 5.08639

165.13840

6440.3901- 5.08639

492.369 - 193.254

1

2.495
90

222.087

0.885

0.015

2.678
90

238.352

0.266

0.119

3.221
90

286.648

0.067

0.194

Insulin- 17.970 - 193.254

0.997- 0.001

2.495
90222.087

0.885

0.015

4608.25793

423,959.630

1

50.169934615.574

0.471

0.076

32.377932978.642

0.519

0.068

IGF1