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EFFECTS OF NORTH AMERICAN GINSENG (Panax quinquefolius Le)
ON POSTPR4NDIAL GLYCEMIA IN NORRlAL HUMANS
Vernon Yut Yu Koo
A thesis submitted in conformity with the requirements for the degree of M.Sc.
Graduate Department of Nutritional Sciences University of Toronto
O Copyright by Vernon Yut Yu Koo 1997
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Ei?Fli;CrI'S OF NNOKTH AMERICAN GINSENG (Panax quinquefolius L.)
ON POSTPRANDIAL GLYCEMIA IN NORMAL HUMANS
Master of Science, 1997 Vernon Yut Yu Koo
Graduate Department of Nutritional Sciences University of Toronto
ABSTRACT
To investigate the effects of North Arnerican ginseng (Panax quinquefolius L.)
powder on reducing postprandial glycemia, a glucose challenge of 25 g carbohydrate was
used. Capillary blood was collected at fasting, 15, 30, 45, 60, and 90 minutes afier initial
consumption of glucose challenge.
Ginseng powder (3 g, 6g and 9 g) with glucose challenge, had no significant effect
on blood glucose when compared to glucose alone in healthy individuals (4 males, 4
females). However, when 3 g and 6 g of ginseng powder were ingested 40 or 80 minutes
pnor to glucose dnnk, lower glycemic responses (4 males, 2 females, p < 0.05) were
observed. Lower glycemic response also resulted fiom 9 g Panm quinquefolzus L.
ingested at either 40 minutes (p < 0.01), 80 minutes (p < 0.01), or 120 minutes (p < 0.05)
prior to glucose challenge. This glycemic response was not dose dependent.
It was concluded that Panax quinquefolius L. lowers postprandial glycemia at
levels of 3 g, 6 g, 9 g, and possibly at lower doses, when taken pior to glucose challenge.
In loving memory of my mother, Marie
iii
First, 1 would like to thank my supervisor, Dr. V. Vuksan, for his support and
encouragement. Without his insightful supervision and encouragement, this work would
not have been accomplished. To Dr. T.M.S. Wolever, your invaluable guidance and
suggestions were greatly appreciated. 1 would also like to thank Dr. T. Francis for his
continued support and assistance throughout my program. Special thanks to Dr. A.V.
Rao for being on my Advisory Cornmittee, Drs. D.J.A. Jenkins and S.C. Cunnane for
serving on my Examination Cornmittee, and Dr. T. Heim for being my Appraiser. 1 am
also grateful to Dr. L.U. Thompson for al1 her guidance over the years.
1 am indebted to my fnends who graciously participated in my research
experiments. Without their cornmitment, this study would never have been completed.
Sincere thanks to George Yeung for al1 his encouragement, advice and statistical help, and
Evelyn and Brenda for al1 their help and fun during my studies. 1 am also grateful to the
staff of the graduate department, in particular, Brenda Rak, for keeping me up to date.
Thanks to Atkins Farm Limited and Chai-Na-Ta Corporation for their generous
contribution of ginseng capsules and research information.
Finally, rny deepest thanks to my farnily for their unconditional love and support.
To my father and Auntie Phyllis, your patience and care are greatly appreciated. To Tina
and Clarence, thanks for putting up with me even when 1 was mistrated. To Christina,
thanks for being inexhaustibly loving and supportive throughout.
ABSTRACT ...................................................................................................................
ACKNOWlLEDGMENTS ............................................................................................
......................................................................................................... LIST OF TABLES
LIST OF FIGURES ........................................................................................................
AEIBREVIATIONS ........................................................................................................
CHAPTER 1 . Introduction and Literature Review 1.1 Introduction ............................................................................................ 1.2 Literature Review
1.2.1 History of Ginseng ....................................................................... 1.2.1 . 1 Description ............................................................................ 1.2.1 -2 North American ginseng (Panax quinquefolius L.)
...................................................................................... trade .................... 1.2.1.3 Chinese Perception on North American ginseng
.................................. 1 -2.1 -4 History of North American ginseng use 1.2.1.5 Oriental ginseng: a traditional perspective ...............................
................................... 1 -2.1 -6 Oriental ginseng: a modem perspective ......................................................... 1.2.2 Varieties of the Genus Panax
1.2.3 Active Components in Ginseng ..................................................... .............................................. 1.2 -3.1 Ginseng saponins: ginsenosides
1.2.3.2 Other active ginseng components: polysaccharides, polypeptides, flavonoids ..........................................................
1.2.4 An Overview of the Pharrnacological Effects of Ginseng ................. 1 .2.4.1 Ginseng as an adaptogen ........................................................ 1.2 .4.2 Ginsenosides R,,, and %, ........................................................ 1.2.4.3 Ginseng polysaccharides and peptides ..................................... 1.2.4.4 A biologically active ginseng peptide, a carboxylic acid
and an adenosine ..................................................................... ............................................................................ 1.2.4.5 Human trials
1.2.4.5.1 Adverse effects of ginseng ............................................. .................................................... 1.2.5 Hypoglycemic effects of ginseng
........................................................................ 1.2.5.1 Animal studies ................................................................. 1.2.5.1 . 1 Ginsenosides
1.2.5.1.2 Water (DPG-series) and methanolic (EPG-series) extracts of P . ginseng ..................................................
............ 1.2.5.1.3 Ginseng polysaccharides: glycans and panaxans
Page
. . 11
... 111
... V l l l
ix
X
. . . . . u
Introduction .......................................................................................... 62 Aim .......................................................................................................... 62 Materials and Methods ........................................................................... 62 4.3.1 Composition of glucose challenge and North Amencan ginseng ..... 62 4.3.2 Subject recruitment and profile ................................................... 63 4.3.3 Experimental design .................................................................... 63
................................. 4.3.4 Study procedure and blood sarnple collection 64 4.3.5 Blood glucose analysis .............................................................. 64 4.3.6 Statistical analysis ........................................................................... 65
4.4 ResuIts ....................................................................................................... 65 4.5 Discussion ............................................................................................ 74
CHAPTER 5 . General Discussion and Conclusions 5.1 GeneraI discussion and fbture research ....................................................... 77
.............................................................................................. 5.2 Conclusion 81
APPENDIX ....................................................................................................................... 95
vii
LIST OF TABLES
Page
Table 1.1 Common ginsenosides of Panax ginseng C.A. Meyer and Panax quinquefolius L ..................................................................................... 5
Table 1.2 Nutrient profiles of P . quinquefolius and P . ginseng ............................... 6
Table 1.3 The pharmacological activities of ginseng ............................................... 12
Table 1.4 Yield of Chinese ginseng in China in 1985 .............................................. 13
. . ...................................................................... Table 1.5 Varietles of Panax species 13
............................................................................. Table 1.6 Types of ginsenosides 15
Table 1.7 Ginsenoside contents in different parts of the ginseng plant ..................... 15
Table 1.8 Cornparison of ginsenoside contents of 2-9 year old ginseng roots ......... 18
Table 2.1 Subj ect profile ................................................................................ 42
Table 2.2 Blood glucose concentrations at specific time points. change in blood glucose peak and incremental areas under the curve (AUC) ................... 47
Table 3.1 Subject profile ...................................................................................... 54
Table 3.2 Blood glucose concentrations at specific time points. change in blood glucose peak and incremental areas under the curve (AUC) ................. 58
Table 4.1 Subject profile ..................................................................................... 67
Table 4.2 Two-way ANOVA of the mean differences in AUC among North Amencan ginseng powder. administration tirne. dose and time-dose interaction ............................................................................................ 69
viii
LIST OF FIGURES
Page
Fig. 1 .1 Chemical structures of different ginsenosides ............................................. 17
Fig. 2.1 Effect of North American ginseng taken together with a glucose challenge postprandial glycemic response (n=8) ......................................................... 45
Fig. 2.2 Incremental area under glycemic response curve: North American ginseng taken together with a glucose challenge (n=8) ............................................. 46
Fig. 3.1 Experimental design.. .............................................................. 52
Fig. 3.2 Incremental area under glycemic response curve: North American ginseng taken pnor to a glucose challenge (n=7) ...................................................... 57
Fig. 3.2 Effect of North American ginseng on postprandial blood glucose when taken prior to a glucose challenge (n=7) .................................................... 59
Fig. 4.1 Incremental area under glycemic response curve: 3 g, 6 g, 9 g of North Amencan ginseng powder taken at -40, -80, -120 minutes before a glucose challenge (n=6) ........................................................................... 68
Fig. 4.2 Percent reduction in AUC with different time and dose of North Arnerican ginseng powder administration (n=6) ......................................... 70
Fig. 4.3 Effects of 3 g North Amencan ginseng on postprandial blood glucose ....... when taken at 40,80,120 minutes prior to a glucose challenge (n=6). 7 1
Fig. 4.4 Effects of 6 g North American ginseng on postprandial blood glucose when taken at 40,80, 120 minutes p i o r to a glucose challenge (n=6) ........ 72
Fig. 4.5 Effects of 9 g North Arnerican ginseng on postprandial blood glucose when taken at 40,80, 120 minutes prior to a glucose challenge (n=6). ....... 73
Y0
AUC
BMI
DIOL
Fig
g
GS
IDDM
kg
min
mL
mrnoVL
NDDM
P. ginseng
P. japonicus
P. quinquefolius
S E
T . CHO
TCM
TRIOL
ABBREVIATIONS
Percent
Incremental blood glucose area under curve
Body mass index
Protopanaxadiol
Figure
Grams
Ginsenosides
Insulin-dependent diabetes mellitus
Kilograrns
Minutes
Milli-Litre
Milli-mole per Litre
Non-insulin dependent diabetes mellitus
Panax ginseng C.A. Meyer
Panax japonicus C.A. Meyer
Panax quinquefolius L.
Standard error of mean
Total carbohydrate
Traditionai Chinese medicine
Pro topanaxatriol
CHAPTER ONE
INTRODUCTION
AND
LITERATURE REVIEW
1.1 Introduction
The value of ginseng in promoting overall body health has long been recognized by
the Chinese, who daim to have been using ginseng for 5,000 years [Bloomfield, 19871.
The first known reference appeared in a manuscript from the third century BC, suggesting
that there exists a very long history of ginseng by humans consumption [Bloomfield,
19871. In fact, it was recorded in the first officia1 Chinese pharmacopoeia, Shen Nung Pen
Tsao, published almost 2,000 years ago. However, Shen Nung Pen Tsao was later revised
in fifih century AD and few additions were made which included using ginseng to treat
thirst and poly~ria due to diabetes, to reduce swelling and inflammation, and to increase
memory [Bloomfield, 19871. Despite its long history of medicinal use, ginseng health
beneficial claims are generally based upon anecdotal evidence. It has only been over the
past 20 years or so that some of the many claims are examined scientifically.
Ginseng is the common name of mainly two species of P a n a herbs, belonging to
the family of Araliaceae [Li and Li, 19731. North Arnerican ginseng is botanically known
as Panax quinquefolius L. (P. quinquefolius), while the more extensively studied root,
Chinese or Korean ginseng, is called either Panax schinseng Nees or Panax ginseng C.A.
Meyer (P. ginseng) [Fulder, 19931. The latter name is the more commonly used name for
Oriental ginseng today.
There are various compounds which are believed to be biologically active in the
P u n a species. Triterpenoid glycosides or saponins termed ginsenosides (GS) by Japanese
more studied ginseng components. Chemical analysis shows that both P. quinquefolius
and P. ginseng contain similar types of GS with the only difference being their respective
quantities (Table 1.1). In addition, they also have very comparable nutrient profiles (Table
1.2). Other active constituents include polysaccharides, some of which are termed
panaxans; peptides, a carboxylic acid, adenosine, and flavonoids [Konno et al., 1984;
Tomoda et al., 1984; Konno et al., 1985; Oshima et al., 1985; Zhu et al., 1989; Yang et
al., 1990; Yang and Wang, 19911. However, these compounds have only been confirrned
in Oriental ginseng.
It has been reported numerous times that ginseng components extracted fiom P.
ginseng have hypoglycemic activity in diabetic rodents [Kimura et al., 1981 a; Kimura et
al., 1981b; Kimura and Suzuki, 1985; Waki et al., 1982; Yokozawa et al., 1985; Yang et
al., 1990; Yang and Wang, 1991; Wang et al., 1990a; 1990bl However, the attributes of
ginseng that impact diabetic control in humans are not very well elucidated. Nevertheless,
recent findings by Sotaniemi et al. [1995] indicate that Oriental ginseng extract may be a
beneficial therapeutic adjunct in the management of non-insulin dependent diabetes
mellitus (NIDDM).
Since P. quinquefolius and P. ginseng have similar nutrient profiles, contain
several commonly considered active constituents in common, and Oriental ginseng
components have been demonstrated to be beneficial in diabetic humans and animals, it is
hypothesized that North American ginseng also possesses similar physiological activities
as its Asian cousin. Furthemore, the majority of ginseng research has been conducted on
- - - . A Y u - - - - - - . . - - - - - - 7 -- -- ----
purpose of this study to investigate the efficacy of P. quinquefollis powder ground from
ginseng root hair in lowering postprandial glycemia in humans. Since the dose and
method of administration have not been specified, the results from this study allow for the
determination of the optimal time and dose of administration of North American ginseng.
In addition, the results aIso give light to designing fùrther clinical studies with NIDDM
patients.
Table 1.1 Common Ginsenosides of Panax ginseng C.A. Meyer and Panax
quinquefolius L. '
Type P. ginseng (%) P. quinquefolius (%)
Protopanaxadiol
%i 0.37
%2 0.18
Rb3 0.0 1
% 0.13
O. 13
Protopanaxatriol
R, 0.20
Rd 0.2 1
R@ 0.02
Oleanolic acid
& 0.04
' Sprecher, 1987
Table 1.2 Nutrient Profiles of P. quinquefolius and P. ginseng
Types of Ginseng (per 100g)
P. quinquefolius ' P. ginseng 2
Energy (kcal) 371.2 345.4
T. CHO (g) 67 59
1 Samples supplied by Chai-Na-Ta Corp. and Atkins Farm Ltd. [JR Laboratories Inc., BC, 1997; Industrial Lab of Canada Inc., Ont., 19971 Samples suppIied by Atkins Farm Ltd. [Industrial Lab of Canada Inc., Ont., 19971
1.2.1 History of ginseng
1.2.1.1 Descri~tion
The term, ginseng, is often applied to two Panax species of the Araliaceae family;
Panax quinquefolius L. and Panax ginseng C.A. Meyer [Li and Li, 19731. While Panax
is derived from the Greek word, pan-axos, which literally means all-healing [Owen, 1980;
Fulder, 19931, ginseng rneans 'essence of the earth in the form of a man' [Graham, 19661.
North American ginseng is botanically known as Panax quinquefolius L. (P.
quinquefolius), where L denotes Linnaeus who named the plant. Oriental ginseng
(Chinese or Korean ginseng), on the other hand, was originally named Panax schinseng
Nees by Nees van Esenbeck which was later changed to Pana ginseng C.A. Meyer (P.
ginseng) by Car1 Anton Meyer in 1842 [Fulder, 19931. Today, the Oriental variety is
commonly referred to as Panax ginseng C.A. Meyer.
1.2.1.2 North American pinsenp (Panax quinquefolius L.) trade
P. quinquefolius is native to the nch, rocky, shaded, cool slopes of eastern North
Arnerica, from Quebec to Manitoba of Canada, south to northern Florida, Alabama, and
Oklahoma of the United States [Foster, 19931. Ginseng roots are herbaceous perennials
which have historically been used as a medicinal plant and a trading commodity by al1
native populations in the areas where it was grown [Oliver, 19901.
North Arnerican ginseng (P. quinquefolius) was first discovered in Quebec in 1704
by Michael Sarrasin, the King's Physician to Canada [Hellyer, 19841. The root was later
found again by Father Lafitau, a Jesuit Missionary, near Sault Ste Louis, Quebec in 171 5.
North Arnerican ginseng root was first exported fiom Canada to China by Father Jartoux
[Goldstein, 19751. By 17703, it was recorded that an average of 140,000 pounds ginseng
roots native to North America was exported each year [Foster, 19911. However, near the
turn of the eighteenth and nineteenth centuries, the early substantial profit gained fi-om
trading North Amencan ginseng with China resulted in large quantity of ginseng being
over-harvested and improperly dried in a short period of time [Hellyer, 19841. As a result,
the roots were shipped in such bad condition that it becarne unacceptable to the Chinese
which led to an enormous decline in ginseng trade with China. Exports continued to
decrease as wild ginseng became scarce with the possibility of extinction [Hellyer, 19841.
This situation prompted protective rneasures from the United States government and in
1890 Ontario government adopted the guidelines and prohibited ginseng gathering
between January and September [HelIyer, 19841.
Cultivation of North American ginseng was first attempted in 1890 by George
Stanton at Fabius, New York by transplanting wild ginseng. Soon after this, many
pamphlets were published to provide information on the techniques of growing and drying
ginseng roots [Hellyer, 19841. However, the ginseng industry suffered yet another fa11
during the depression in 1929. It was not until 1940 before export resumed [Hellyer,
19841. Today, P. qguinquefolius has established itself as a major Canadian cash crop
[Thomas, 19961. In 1995, there were approximately 250 ginseng growers producing 2.1
million pounds of dried ginseng root, valued at $40 a pound. The total crop vaIue was
$84 million. The major market for the crop remains Asia [Thomas, 19961.
1.2.1.3 Chinese perception on North American ginseng
Chinese are the greatest ginseng consumers in the world [Schreiner, 19951. They
favour P. quinquefolius for several reasons. First, when the North Amencan root was
initially exported to China, wild P. ginseng had already become extremely scarce. Asians
believe that United States manufactured or produced goods to be of superior quality. The
taste of P. quinquefolius is sweeter than its Asian variety. In addition, P. quinquefolzus
and P. ginseng are considered to possess distinct rnedicinal properties. P. quinquefolius is
considered more yin in TCM which means that it is good to reduce heat for cooling of the
respiratory or digestive systems. P. ginseng, on the other hand, is more yang and is a
heat-raising or stimulating tonic for the blood or circulatory system. As a result, P.
quinquefolius is preferred by Asians as it is a cold or mild tonic that will reduce " heat " in
the system, while acting as a general tonic.
1.2.1.4 History of North American ins sen^ use
The use of P. quinquefolius by native groups was not very well documented.
However, it was one of the five most important medicines among the Seneca Indians,
primarily used by the elderly. Crow Indians used it to induce childbirth without suffering
[Goldstein, 19751. The Oklahoma Seminole used the root to cure nosebleed and treat
shortness of breath [Howard, 19841. Penobscots drank the water extract of the root to
increase fertility in women [Speck, 191 51. Although Ojibwe had not been observed to use
the root, they harvested it for sale.
1.2.1.5 Oriental pinsene: a traditional ~erspective
Chinese or Korean ginseng (P. gznseng) is the most popular Panax species and has
been investigated substantially more than its North American cousin. This variety of
ginseng has been used for 5,000 years in the Orient as a tonic, prophylactic agent and
'restorative' [Goldstein, 1975; Hu, 1977; Bloomfield, 19871. In fact, it has been recorded
in the first Chinese pharmacopoeia, Shen Nung Pen Tsao, published alrnost 2,000 years
ago that P. ginseng 'soothes base emotions, safeguards the soul, drives out fear, expels
evil influences, brightens the eye, opens up the heart, increases the spirit, and if taken over
a long period of tirne, prolongs life' [Bloomfield, 19871. In traditional Chinese medicine
(TCM), this explanation indicates that ginseng affects liver and kidney functions, heart and
blood circulation, and treats diseases associated with exposure to "cold" or yin conditions,
such as body aches and pains, muscular contraction, diarrhea, nausea, indigestion, and
influenza [Bloomfield, 19871. However, Shen Nung Pen Tsao, was later revised in fifth
century AD by T'ao Hung-ching. Additional health conditions were attributed to Oriental
ginseng, including treatment of thirst and polyuria due to diabetes, reducing swelling and
inflammation, and increasing memory capacity [Bloomfield, 19871.
In 1552 AD, a famous herbalist, Li Shih-chen (1 5 18-1593), compiled al1 the
knowledge contained in thousand of volumes of herbal knowledge in China into a 52-
volume pharmacopoeia called Pen Tsao Kang Mu [Bloomfiled, 19871 in which ginseng
was described in detail [Li et al., 19731. This collection was completed by Li's son afler
his death and was published for the first time in 1578. In fact, it is still in print today and
ingredients used in medical treatments - herbs, roots, minerais, and animal products - but
also over 8,000 prescriptions [Bloomfield, 19871.
1.2.1.6 Oriental ginsenp: a modern ~ e r s ~ e c t i v e
Due of its long history of use, P. ginseng has been the focus of most ginseng
scientific investigations. As a consequence, Oriental ginseng is the most studied Panax
species. Over the past 20 years, many of the traditional claims associated with this root
have been studied scientifically. Many scientists worldwide have confirmed some of its
attributes in animals (Table 1.3). In addition, there is also a rapidly increasing demand for
ginseng which has warranted special efforts on the development of ginseng cultivation in
China [Liu and Xiao, 19921. This leads to substantial improvement in the quality and
quantity of ginseng produced. The total natiional yield of ginseng in 1985 was recorded as
1560.9 tons in China (Table 1.4) [Yu, 19871.
1.2.2 Varieties of the Penus Panax
Several Panax species are known to exist (Table 1.5) [Barna, 1985; Liu and Xiao,
19921 based on their place of origin. There are also other plants which are similar to the
Panax species in appearance but are, in fact, botanically different despite belonging to the
same family of Araliaceae. One of the well-known examples of this is Siberian ginseng or
Eleutherococcus senticosus [Hou, 1977; Phillipson and Anderson, 1984; Bahrke
Table 1.3 The Pharmacological Activities of Ginseng -- -
Protection against radiation and liver toxicities '4
Modulation of cardiovascular system '" Decrease platelet aggregation 'O-''
Changes in blood flow 8~14~15
Improvement or facilitation of learning and memory processes l6
Anti-stress activity l6
Modulations of endocrine and immune systems 16-18
Modulation of cellular metabolic processes on carbohydrate, fat and protein metabolism l6
' Yonezawa et ai., 1976 Takeda et al., 1981 Yonezawa et al., 1981; 1985 Takeda et al., 1982 Zhang et al., 1987
6 Wood et al., 1964 Lee et al., 1981 Chen et al, 1984 Lei and Chiou, 1986
'O Matsuda et al., 1986a; 1986b l ' Kimura et al., 1988 l2 Matsuda et al., 1989 l 3 Teng et al., 1989 l4 Kaku et ai., 1975 l5 Hata et al., 1985 l6 Liu and Xiao, 1992 l7 Komo et al., 1984 l 8 Konno et al., 1985
Location Yield (tons)
Jilin
Liaoning
Heilongi iang
Total
Table 1.5 Varieties of Panax Species 2L
Botanical Name Common Name
1 Panax quinquefolius L. North American ginseng
2 Panax ginseng C.A. Meyer Chinese or Korean ginseng
3 Panax japonicus C .A. Meyer Japanese ginseng
4 Panax nologinseng F.H. Chen White ginseng
5 Puna pseudoginseng W dl. NIA
6 Panax zingiberensis C .Y. Wu et K.M. Feng NIA
7 Panax stipuleanatus H.T. Tsai et K.M. Feng NIA
NIA - not available
' Yu, 1987 Barna, 1985 Liu and Xiao, 1992
diflerent plants. As a result, the confusion of botanical names is an indication of the
general usage of the word, ginseng.
Although there are many varieties of ginseng, only three species are currently
considered to be medicinally active. They include P. quinquefolius (North American
ginseng), P. ginseng (Chinese or Korean ginseng), and P. japonicus (Japanese ginseng)
[Williams, 1957; Court, 1975; Phillipson and Anderson, 19841. The former two varieties
have similar compositions of nutrient and certain active components (Tables 1.1; 1.2).
However, P. japonicus only shares two common active constituents with P. quinquefolius
and P. ginseng (Section 1.2.3.1) [Bahrke and Morgan, 19943. Despite this difference, P.
japonicus has been used as inexpensive substitutes for the dried root of P. ginseng
[Bahrke and Mogan, 19941. At present, both P. quinquefolius and P. ginseng are sold
worldwide in forms of processed roots, powders, teas and capsules [Liberti and
DerMarderosian, 19781.
1.2.3 Active Components in Ginseng
1.2.3.1 gins en^ saponins: pinsenosides
Many ginseng experts consider ginseng saponins to be the primary biologically
active components of Panax species [Hou, 1977; Phillipson and Anderson, 1984; Liu and
Xiao, 1992; Bahrke and Morgan, 19941. They are known as ginsenosides (GS), of which
28 (Table 1.6) have so far been identified fiom the root, root-stock, stems, leaves, flowers
and flower-buds of the P. ginseng plant (Table 1.7) [Zhang et al., 1979; 1980; Cai et al.,
1982; Kuang and Xu., 1982; Shao and Xu, 1982; Wang et al., 1983; Wang et al., 1986;
Protopanaxadiol Protopanaxatriol Oleanolic Acid
Table 1.7 Ginsenoside Contents in Different Parts of Ginseng Plant ' Part Protopanaxadiol Protopanaxatriol Oleanolic Total Amount
Type (9 Type (%) TY pe (%) (%)
Root 1.1 1 2.19 0.89 4.19
Leaves 1.62 3 .O0 3 .O2 7.64
' Zhang et al., 1979; 1980 Cai et al,, 1982 Kuang and Xu, 1982 Shao and Xu, 1982 Wang et al., 1985 XU et al., 1986a
' XU et al., 1986b, 1986c
dammarane series. They are named Rx, where x is either a letter, or a number, or both,
according to their position on thin layer chromatogram [Phillipson and Anderson, 19841.
According to their chemical structure characteristics, they can be fiirther divided into three
types: oleanolic acid (OA), protopanaxadiol (Diol) and protopanaxatriol (Triol) (Figure
1.1) [Sprecher, 1987; Liu and Xiao, 19921.
Both P. ginseng and P. quinquefohs contain ginsenosides bl, &, Rb3, ]Rc, and
& as Diols; &, Rg1, and Rg2 as Triols; and R,, as OA (Table 1.1) [Sprecher, 19871.
However, they have different composition of GS. For instance, ginsenosides & and Rf
while present in P. ginseng are absent in P. quinquefoIius [Hou, 1977; Sprecher, 19871.
In addition, the approximate ratio of Di01 to Triol of North American ginseng root is
about 6.5 to 1 . On the other hand, this ratio is close to 1 in Oriental ginseng [Hou, 19771.
Accordingly, P. quznquefolius contains substantially more Di01 than P. ginseng. This can
be used to explain why the Chinese believe that American root has different physiological
effects fiom its Chinese cousin [Hou, 19771.
P. japonicus is one of the most famous P. ginseng substitutes ever used in Japan.
Its GS profile is very much different fiom both P. ginseng and P. quinquefolius. It was
reported that the Japanese root contains mainly different saponins. Only ginsenosides Rg2
and & are common to Japanese, Chinese or Korean and American ginsengs [Bahrke and
Morgan, 19941.
There are several factors that affect the amount of GS in the Panax plant. GS exist
not only in the root but also in other parts such as stems, root stock, leaves, flowers and
flower-buds. In fact, it was illustrated that the quantities of GS varied in
20s protopanaxadiol ginsenosides
H
\ 20s protopanaxatriol ginsenosides
Figure 1.1 Chemical structures of différent ginsenosides
Table 1.8 Cornparison of Ginsenoside Contents of 2-9 Old Ginseng ' -- -
Years Total Rb R, R0 Ginsenosides (%) (%) (%) (%)
Zhang et al., 1980
fi . U --r ----- --- J --- va - - - - - -
growth, lowest at two years and reduce after the sixth year [Zhang et al., 19801. This
suggests that the collection period is crucial to its GS quantity which is indicative of the
quality of ginseng.
1.2.3.2 Other active pinsenp: components: ~olysaccharides, ~olypeptides,
flavonoids
Aside from GS, there are other physiologically active principles in ginseng. They
include polysaccharides, polypeptides, a carboxylic acid, adenosine and flavonoids [Konno
et al., 1984; Tomoda et al., 1984; Konno et al., 1985; Oshima et al., 1985; Zhu et al.,
1989; Yang et al., 1990; Yang and Wang, 19911. Ginseng glycans, a type of
polysaccharides, are referred to as panaxans [Konno et al., 1984; Tomoda et al., 1984;
Konno et al., 1985; Oshima et al., 19851, The flavonoid constituents are identified as
kaempferol, tnfolin and panaxasenoide on the basis of chernical and spectroscopic analyses
[Wang et al., 2 9861. However, these compounds are only isolated from P. ginseng and
have not been confirmed in other ginsengs.
1.2.4 An overview of ~harmacoloeical effects of ~inseng
1.2.4.1 Ginsen? as an ada~togen
Very few pharmacological and clinical studies have been conducted with North
American ginseng, despite its similarity to Oriental ginseng (Tables 1.1 ; 1.2). In fact, the
majority of scientific investigations on ginseng were done primarily with P. ginseng in the
past 20 years. Since the nutrient contents and certain active components are common in
Y d - - - - - . . - - - - - , ------ -".Y'-' r--J Y-V.Vb.YU.
properties,
In 1970's ginseng was pharmacologically classified as an adaptogen, by Russian
pharmacologists Brekhman and Dardyrnov [1969a]. They defined it as 'a non-specific,
innocuous substance which improves the resistance of the organism to the most varied
fonns of stress and by its regulating actions restores, revitalizes or enhances homeostasis'.
They also concluded that the basic effect of ginseng action was its potential capacity to
increase non-specific resistance to various stressors [Brekhrnan and Dardyrnov, 1969bI.
Since then, P. ginseng had been associated with a variety of other physiological effects
mostly in animals by other investigators (Table 1.3).
1.2.4.2 Ginsenosides Rb* and R,I
The majority of the pharmacological effects of ginseng listed in Table 1-3 have
been attributed to GS. Among al1 the GS that have been identified, ginsenosides hl and
RgI, which are Di01 and Triol respectively, have attracted much of the attention. Although
both P. quinquefolius and P, gznseng contain RI,^ and Rgl, hi and Rgl are the most
abundant respectively in P. quinquefolius and P. ginseng (Table 1.1) [Sprecher, 1987;
Chuang et al., 19951. Early research suggested that Rb1 suppressed central nervous system
(CNS) activity and had tranquilizing properties, while Rgl possessed slight CNS
stimulation, and vasodilator activities [Takagi et al., 1974; Owen, 198 1 ; Bahrke and
Morgan, 19941. As hl and Rgl CO-exist in both North American and Oriental roots, these
findings seem to support the hypothesis that ginseng acts as an adaptogen which provides
homeostasis [Brekham and Dardyrnov, 1969a; 1969bI.
1.2.4.3 gins en^ ~olvsaccharides and pe~tides
Ginseng polysaccharides and peptides were also shown to be physiologically
active. The polysaccharides were found to markedly stimulate phagocytosis of the
reticuloendothelial system and the production of antibodies [Wang et al., 19801 and had
hypoglycemic activity [Konno et al., 1984; Tomoda et al., 1984; Konno et al., 1985;
Oshima et al., 1985; Yang et al., 1990; Yang and Wang, 199 11. It was reported that these
polysaccharides increased serum complement content in guinea pig, raised serum
immunoglobulin G level in mice, and elevated B-lyrnphatic to T-lymphatic ce11 ratio [Wang
et al., 19801. Consequently, ginseng polysaccharides seem to affect immune fbnctions.
Furthemore, ginseng glycans and peptides extracted fiorn P. ginseng were demonstrated
to have hypoglycemic activity in normal and drug-induced diabetic mice [Konno et al.,
1984; Tomoda et al., 1984; Konno et al., 1985; Oshima et al., 1985; Yang et al., 1990;
Yang and Wang, 19911.
1.2.4.4 A biolo~icallv active ins sen^ ~eptide, a carboxvlic acid and an
adenosine
A peptide with a molecular weight of 1400 [Ando et al., 1979; 19801, a carboxylic
acid [Sekiya et al., 19811 and adenosine [Okuda and Yoshida, 1980; Sekiya et al., 19801
isolated fiom the water extract of P. ginseng were reported to be insulin-like and have
anti-lipolytic properties. The carboxylic acid inhibited lipolysis induced by epinephrine and
thyrotropin [Sekiya et al., 19811. Ginseng flavonoids were reported to influence cardiac
performance and hernodynarnics [Pan and Zhang., 19861.
1.2.4.5 Human Trials
Only a few controlled experiments in humans have been reported. Hallstrom et al.
tested the effects of 1.2 g Korean ginseng or P. gznseng on 12 night-shifl nurses, using
placebo and a good night's sleep as controls in a double-blind, crossover trial [Hallstrom
et al., 19821. Mood and body feelings were assessed before and after each treatment
phase. The results indicated that there was no significant differences between placebo-
and ginseng-treated phase in any of the parameters measured. However, a trend was
noted, especially for mood ratings in ginseng-treated phase. As a result, the authors
concluded that the duration of the study (2 weeks) and the low dosage of ginseng used
might have influenced the outcome. Although blood sugar showed a decline in the
experimental group, this reduction was not significant and the observed levels were in the
normal range before and during the treatment.
McNaughton et al. tested Chinese and Sibenan ginsengs on 30 athletes (15 males
and 15 females) who were randornly assigned to either placebo, or Siberian ginseng, or
Chinese ginseng group [McNaughton et al., 19891. They were instructed to ingest 1 g of
the substance at 8:00 a.m. each rnorning for six weeks. Results showed that Chinese
ginseng- or P. ginseng-treated group had a significantly improved maximal oxygen uptake
when compared to placebo control, while the Siberian ginseng treated group did not differ
recover as indicated by a lower post exercise heart rate, whereas Siberian ginseng had no
difference. These results suggested that Oriental ginseng seemed to be beneficial to
humans, a conclusion that remains controversial.
Engels et al. (1 996) conducted a randomized, double-blind, placebo-controlled
study in which 19 healthy adult females were administered 200 mgld of a concentrated
extract of P. ginseng (n = 10) or placebo (n = 9) to their othenvise supplement-fiee
normal diet. Before and afler the trial intervention, subjects performed a graded maximal
cycle ergometry test to exhaustion and completed a standard habitua1 physical activity
questionnaire. Blood was analysed for lactic acid. It was found in this study that
standardized extract of P. ginseng had no influence on any of the variables measured and
as a result, the authors concluded that Oriental ginseng did not enhance work
performance, change energy metabolism, improve recovery response fiom maximal
physical work.
Recently findings by Cui et al. and Hasegawa et al. demonstrated that ginseng
saponins or GS are detectable in blood [Cui et al., 19961, urine, and feces [Hasegawa et
al., 19961 in human athletes who consumed ginseng preparations orally. These findings
indicate the uptake of ginseng saponins in humans afier oral administration of ginseng
preparations.
1.2.4.5.1 Adverse effects of pinseng
The stimulant effects of ginseng and the potential problems associated with the
long term effects of the use of ginseng, primarily CNS excitation and arousal, were given
the name, Ginseng Abuse Syndrome (GAS) by Siegel [1979]. GAS was defined as
hypertension together with nervousness, sleeplessness, skin eruptions, edema and morning
diarrhea. The range of daily dosage for individuals experiencing this syndrome was found
to be O to 15 g. Siegel claimed that GAS was sirnilar to organic brain syndromes
associated with corticosteroids and corticotropin and might be related to ginseng's
interference with cortisone and corticotropin levels. However, Siegel's views were based
entirely upon self-reported data obtained in a survey of ginseng users as opposed to a
controlled, experimental trial. In addition, Siegel clearly stated that the subjects
consumed a wide variety of commercial ginseng preparations. Therefore, GAS cannot be
assigned solely to ginseng in general.
1.2.5 Hvpoglvcemic effects of pinseng
1.2.5.1 Animal studies
1.2.5.1.1 Ginsenosides
Ginseng has been suggested to have a synergistic action with insulin and also its
own hypoglycemic activity. Yokozawa et al. [1985] showed that a semi-purified saponin
fraction fiom P. ginseng could stimulate various metabolic reactions involved in lipid and
sugar metabolism in normal rats. Other reports indicated that most of the biochemical
actions of the semi-purified saponin extract might due to ginsenoside Rb2 [Yokozawa et
al., 19841. Administration of Rb2 to streptozotocin-induced diabetic rats improved
I I Y I L - - ----- -- ------ ----
had a significant rise of glucokinase activity in the liver and a significant decrease in
glucose-6-phosphatase. This also associated with an increase in hepatic glycogen. As a
result, it was concluded that might elicit its hypoglycemic activity by changing the
levels of gluconeogenic and glycolytic enzymes and shifting the direction of the overall
metabolic flow toward glucose oxidation. The results suggested that the administration of
& to diabetic rats stimulated the lipolytic activity of lipoprotein lipase, with a
corresponding decrease in serurn triglycerides (TG) and very low density lipoprotein
(VLDL). This indicated that RI,^ might play a role in facilitating the re-esterification of TG
fatty acid and glucose in the adipose tissue [Yokozawa et al., 19851. Consequently, the
work provided some evidence that ginsenoside %2 might be a usefùl hypoglycemic agent
and that its action was very similar to the rnetabolic alterations produced by insulin.
1.2.5.1.2 Water (DPGseries) and methanolic (EPGseries) extracts of P.
ginseng
Kimura et al. [1981a; 19821 and Waki et al. El9821 demonstrated that the water
(DPG-series) and methanolic (EPG-series) extracts fiom P. ginseng had hypoglycemic
activity in alloxan diabetic mice injected i.p. with the ginseng fraction. These extracts were
first fiactionated with a water-diethyl ether mixture, then the water layer was further
treated with n-butanol, and the butanol layer was dialyzed. The outer dialyzates yielded
the hypoglycemic extracts called DPG-3-2 and EPG-3-2. EPG-3-2 was reported to
increase blood insulin secretion in normal and diabetic mice [Waki et al., 19821. The
hypoglycemic activity of EPG-3-2 in diabetic mice was abolished by an insulin antiserum,
was found to modiQ the metabolic clearance of insulin. Simultaneous perfusion of the
pancreas with DPG-3-2 and glucose was also s h o w to produce an additive effect on
insulin release in both normal and diabetic rats [Kimura et al., 1981bj. These findings
seemed to suggest that some ginseng fractions could stimulate insulin release, especially
glucose-induced insulin release fiom pancreatic islets, and thereby lowered blood glucose
level [Waki et al., 19821. Furthermore, although both EPG-series and DPG-series extracts
had yet to be fùlly chernically characterized, chemical analyses on these extracts indicated
that these ginseng fractions consisted of unknown substances as major components and
ginseng saponins as minor components, with EPG-series containing more saponins
wmura et al., 1981 a]. However, neither one of them was more effective in lowering
blood glucose than the other, suggesting that the hypoglycemic effect of ginseng fiaction
might not be due to the saponins present as minor components [Kimura et al., 1981al.
Therefore, the hypoglycernic component might be a new principle different fiom GS.
Kimura et al. [l98 1 a] a h andyzed the glucose tolerance curves of hyperglycemic
KK-CAY mice. A comparison was been made between mice receiving a blended Chinese
traditional medicine without ginseng and mice receiving the same medicine with added
ginseng extract, DPG-3-2. It was observed that the mixture with DPG-3-2 decreased the
rise in glucose tolerance curve, indicating that blood glucose was cleared out of circulation
at a faster rate. However, the chernical structure of the active principle in DPG-3-2 had
not been filly elucidated.
--------- --------- --.- r YI----..- -UV". hl 7 YU.." WU...," ,a'... U,.U.IJ
Aside £Yom GS, ginseng polysaccharides were found to exhibit hypoglycemic
activity. Konno et al. [1984] were the first to isolate these polysaccharides or glycans
fiom an aqueous methanoywater extract of P. ginseng. There were currently ten
hypoglycemic glycans recognized which were given the names panaxan A, 13, C, D, E, Q,
R, S, T, and U [Konno et al., 1984; Konno et al., 1985; Oshima et al., 19851. Out of
these 10 panaxans, only panaxan A was chernically characterized [Tomoda et al., 19841.
'H-NMR spectroscopy confirmed that panaxan A was composed mainly of a- l+6 linked
D-glucopyranose residues having branching at the C3 position. However,
spectrum suggested that these cc-glucose units were also linked at the 1, 3, and 6 position
[Tomoda et al., 1 9841.
Al1 of the panaxans were demonstrated to have hypoglycemic response when
injected i.p. into normal mice [Konno et al., 1984; Konno et al., 1984; Oshima et al.,
19851. In addition, Panaxans A, B, and U, when administered i.p. in alloxan-induced
hyperglycemic rnice, lowered plasma glucose level.
The hypoglycemic capability of ginseng polysaccharides was confirmed by Yang,
1990; Yang and Wang, 19911. This group showed that the administration of ginseng
polysaccharides i.p. and S.C. in mice reduced blood glucose and liver glycogen. They also
found an association of ginseng polysaccharides with increases in adenosine-3',5'-cyclic
monophosphate (CAMP) and adenyl cyclase (AC). This action, however, was completely
antagonized by propranolol, an adrenergic P-receptor inhibit or. In addition, both pyruvate
and the activities of succinate dehydrogenase and cytochrome oxidase were found to
suggested that the action of the polysaccharides extracted fiom P. ginseng was related to
adrenergic receptors causing the production of CAMP which in turn activated the break
down of glycogen for aerobic energy production. In fact, the authors believed that the
polysaccharides might stimulate the release of insulin which led to a reduction in blood
glucose and improvement of diabetes control.
1.2.5.1.4 Ginsenp a o l v ~ e ~ t i d e
Wang et al. [1990a; 1990bl reported that ginseng polypeptide extracted from P.
ginseng possessed similar effects as ginseng polysaccharides. When ginseng polypeptide
was administered Z.V. to rats, blood sugar levels and liver glycogen decreased. When mice
were injected SC. daily for seven consecutive days, ginseng polypeptide also reduced
blood glucose and liver glycogen. However, just like ginseng polysaccharides, this effect
was inhibited by pretreatments of pentolamine and propranolol, suggesting that the effect
of ginseng polypeptide on glucose metabolism rnight be related to adrenergic receptors.
In addition, raised plasma glucose concentrations induced by adrenaline, glucose, or
alloxan were ameliorated by ginseng polypeptide. At doses of ginseng polypeptide which
caused decreases in blood glucose and liver glycogen, ginseng polypeptide also inhibited
lactate dehydrogenase activity and stimulated the activities of the tricarboxylic acid cycle
enzymes, succinate dehydrogenase and cytochrome oxidase. As a result, ginseng
polysaccharides and polypeptides are very similar in their effects on hyperglycemia.
There have been very few well-controlled clinical studies on ginseng. However,
Sotaniemi et al. [1995] recently demonstrated in a double-blind placebo-controlled study
consisting of 36 non-insulin dependent diabetes mellitus patients that P. ginseng extract
elevated mood, improved psychophysical performance, reduced fasting blood glucose
(FBG), decreased body weight, and improved glycosylated hemoglobin (HbAic), serum
aminoterminalpropeptide (PIIINP), and physical activity. In addition, they reported that
serum immunoreactive insulin (RI) and lipids were not affected by ginseng therapy.
The authors suggested that the mechanisrn for improved FBG associated with
ginseng may be multifact orial. They indicated that positive changes in psychophysical
performance improved motivation for self-management, leading to changes in diet and
physical activity. FBG reduction without changes in IR1 suggested improved insulin
sensitivity, while decreases in P I I N by ginseng indicated reduced collagen synthesis
and/or improved elimination, which might prove to be anti-antherogenic. Consequently,
the authors concluded that ginseng which activated mood and psychophysical performance
might improve glucose balance.
1.2.6 Mechanism
1.2.6.1 Anti-stress activities of Ginseng
A majority of early scientific research on ginseng were conducted on its stress
resistant capability in the attempt to explain its adaptogenic properties. The homeostatic
effect of ginseng is different from that of stimulants in that while stimulants affect
, y - - U - - - - - - - - - - - - - - ---- ------- J ------- ---- -- C)-"'""' -Y
faced with a challenge or stress [Fulder, 19811. Pharmacological studies, primarily with
rodents, showed that ginseng or its active components prolonged survival to different
types of stress prekhrnan and Dardymov, 1969a; 1969bl. Physical stress, such as
exposing animals to very hot or cold environments, lethal X-rays, excessive physical work;
chernical stress, such as subjecting animals to medications, poisons, narcotics, toxic anti-
cancer drugs; and biological stress, such as bacterid infections, malaria, surgery,
implantation of cancer, and artificially induced diabetes have al1 been used for more than
twenty years to study the capability and the mechanism of ginseng in eliciting its
adaptogenic properties, and to evaluate its efficacy as claimed by TCM [Fulder, 19931.
1t has generally been agreed that the ability of ginseng to restore homeostasis when
the organism is subject to stress is closely related to the control of the stress hormones. It
is known that corticosteroids and adrenocorticotropic hormone (ACTH) bind directly to
brain tissue in order to increase mental activity during stress and challenge. Fulder El9811
showed that in rats which had been both adrenaIectomized and ovarectomized,
administration of ginseng saponin mixture i.p. for seven days caused a substantial increase
in binding of corticosteroid in lower brain regions two hours after the injection of tritiated
corticosterone. The purpose of removing the adrenal glands and avaries fiom the rats was
to retard the interna1 production of corticosterone. However, when radio-labeled
dexamethasone, a glucocortical analogue, was used instead of corticosteroid, no
differences were observed between ginseng-treated and control rats. This suggested that
ginseng bound specifically on corticosterone. Although the increase in binding of
- - - - - - -- -- . ------- - - --- --- - --- ---- -----
injection due to reduced corticosteroid degradation in the liver, an analysis of cytochrome
P450 activity in the liver did not supported this possibility. In addition, an experiment on
the content of receptor molecules in neurons of the hippocampus showed that there were
similar quantities of receptor in ginseng- and saline-treated rats. As a consequence, Fulder
suggested that there might be an interference with the feedback control of steroid levels in
the body which was established by the hypothalamus, through the pituitary.
Indeed, other investigators also found that GS acted on the pituitary-
adrenocortical system. Using radioimrnunoassay and cornpetitive protein binding method,
Hiai et al. [1979] demonstrated the injection of ginseng saponin mixture i.p. increases
plasma ACTH and corticosterone at 30, 60, and 90 minutes afier the treatment. Isolated
GS, Di01 or Triol, also elevated plasma corticosterone. However, the ginseng-induced
increase in plasma corticosterone was suppressed by pretreatment with dexamethasone.
Hïai et al. Cl9791 concluded that ginseng saponin acted on the hypothalamus andor
hypophysis primanly, and stimulated ACTH secretion which resulted in increased
synthesis of corticosterone in the adrenal cortex.
Fulder [1981] proposed that the adaptogenic or harmonizing nature of ginseng
involved stress steroids. M e r the ingestion of ginseng, the hypothalamus became more
sensitive to stress hormones. When stress occurs, the sensitized hypothalamus acted on
the pituitary to produce large amounts of ACTH which, in turn, acted on the adrenal
glands to manufacture more stress steroids. If stress is prolonged, the sensitized
hypothalamus would detect the level of stress steroids in the body and shut down the
, - - - - -. - - -, . - - - - - - - - - -, ----- - - r r v v u ~ rv vvriuui v v
stress hormones during stress and shut down more quickly when stress stopped. Fulder
[ 198 11 further indicated that the active principles for the regulation of intemal harmony
were GS which were quite sirnilar to steroids in chernical structure (Figure 1.1).
1.2.6.2 Diabetes Mellitus
Non-insulin diabetes mellitus (NIDDM) affects between 5 and 20% of the
population in Western industrialized societies [Harris, 19891 and is associated with a
significant amount of morbidity and mortality [Assmann and Schulte, 19881. However,
there still exist many uncertainties with regards to the pathogenesis of the disease despite
decades of investigative efforts. It has recently been suggested that NIDDM may be more
related to the abnormalities in fat than carbohydrate metabolism [McGarry, 19921.
Approximately 85% of NIDDM patients in the United States are obese [Lillioja et
al., 1988; Eriksson et al., 19891 and that obesity is associated with increased lipolysis,
reflected by increased systernic glycerol and FFA concentrations [Gorden, 1960; Reaven
et al., 19601. In addition, obesity is also associated with insulin resistance, which has been
suggested to be the earliest detectable metabolic defect in patients with NIDDM [Lillioja
et al., 1988; Eriksson et al., 19891. It was shown in both animals and humans that weight
gain decreased insulin sensitivity and glucose tolerance, while weight loss increased them
[Goto et al., 1954; Schliack, 1954; Sims et al., 1973; Pascoe and Storlien, 19901 . It
remains unclear, however, how obesity causes insulin insensitivity. Nevertheless, it was
shown that elevated plasma FFA inhibited insulin-stimulated glucose uptake in healthy
---- J - - - - ---- - - -- - ---- L- - - --- - - -- . y - - - ' J ' ---------- , -- -- -.---*-. -**Wb
physiological elevations of plasma FFA levels lower peripheral insulin sensitivity.
In insulin-dependent diabetes mellitus (IDDM), excess lipolysis is often associated
with hypoinsulinernia. However, adequate insulin therapy usually nomalizes plasma FFA
and triglycerides (TG) levels [Amer et al., 19801. As a consequence, NIDDM differs in
that it is linked to excess lipolysis and hepatic reesterification of FFA to TG which
contributes to high density lipoprotein (HDL) lowering [Kissebah, 1976; Kissebah et al.,
1982; Yki-JaMnen et al., 19891. Although therapeutic intervention may improve
glycemic control in NIDDM, lipoproteins abnormalities usually persist and thereby,
increases the risk of atherosclerosis [Hollenbeck et al., 19861.
1.2.6.3 Possible Mechanism of Ginsen? in Lowering Postprandial Glvcemia
Glucocorticoids are hormones that also pIay a role in the regulation of
carbohydrate metabolism in addition to insulin. Although the complex actions of these
steroids secreted fiom the adrenal cortex are not completely understood, their effects on
carbohydrate metabolism are to facilitate glucagon in its gluconeogenetic action during
fasting. They also inhibit glucose uptake into various peripheral tissues [Moffett et al.,
19931.
Glucocorticoid concentrations Vary throughout the day [Dinneen et al., 19931. In
fact, plasma level of cortisol increases substantially during sleep. As a consequence,
plasma cortisol in the morning has been found to be acutely elevated [Dinneen et al.,
19953. High levels of glucocorticoids or counter-regulatory hormones in plasma lead to
affect glucose uptake [Randle et al., 19631.
When an animal or human is exposed to stress, such as homeostatic stress in the
case of fasting, secretion of ACTH is elevated which brings about a corresponding
increase in glucocorticoids [Moffett et al., 19931. Therefore, elevated leveis of
glucocorticoids are also associated with stress to the body. Durhg an overnight fast, the
body has continuously been exposed to homeostatic stress which results in an elevation of
glucocorticoids. The administration of North American ginseng sensitizes the
hypothalamus by its GS content which, in turn, detects the high level of glucocorticoids
and shuts down their production quickly [Fulder, 19931. With the rapid decline of
glucocorticoids, insulin senstivity improves. Consequently, when a meal is ingested, the
body is prepared or stimulated to clear the postprandial rise in blood glucose out of the
circulation more efficiently. This is not only useful in normal humans, it may also be
helpfùl to NIDDM patients in their daily blood glucose and lipid management.
1.2.7 Conclusion to Literature Review
Ginseng has been used for several thousand of years in China as a tonic,
prophylactic agent and 'restorative'. However, its traditional claims on enhancing overall
body health have been established primarily through clinical or anecdotal experience as
opposed to scientific verification of its pharmacological effects. In the past 20 years,
rnuch scientific research has been conducted on animals to evaluate the efficacy of
ginseng, while there have been very few well-controlled studies on humans. In addition,
Y Y . " u, - - - --- ------ -.--*v".
Chemical analyses show that P. ginseng and P. quinquefolizrs have many GS in
common which are considered to be the active ginseng components responsible for many
pharmacological effects, including improvement of hyperglycemia in diabetic rats. The
hypoglycemic effect of ginseng has been repeatedly demonstrated in animals. In humans,
however, there have been few studies until the recent publication by Sotaniemi et al.
(1995) who showed with NIDDM patients that ginseng extract could elevate mood,
improved psychophysical performance, reduced FBG, decreased body weight and
improved HbAlc, serum PIIINP, and physical activity. This is perhaps the first
demonstration of ginseng efficacy in NIDDM management in humans.
As a consequence, recent findings suggest that Oriental ginseng may be beneficial
in controlling NIDDM. It, however, remains unclear whether North American ginseng
possesses similar physiological effects in humans as the Oriental root despite the simiIarity
of their chemical and nutrient profiles (Tables 1.1, 1.2). Furthemore, it is also uncertain
what the optimal dose and tirne of administration are for either ginseng type. Therefore,
there exists a need to investigate whether whole North Arnerican ginseng root or P.
quinquefolius have any effects on postprandial blood glucose in normal humans and to
determine what the most optimal time and dose of administration are before conducting
studies on NIDDM with North American ginseng root.
1.3 Research Hv~othesis and Obiectives
The hypothesis is that North American ginseng or P. quinquefolius Iowers
glucose challenge.
The main objectives are:
1. To determine whether P. quinquefdlnrs causes a lower postprandial blood glucose
response when taken together with a glucose challenge.
2. To determine if Nonh American ginseng lowers postprandial glycernic response when
taken before a glucose challenge.
3. To determine the most optimal time and dose of administration of North American
ginseng in lowering postprandial glycemia.
CHAPTER TWO
EFFECTS OF NORTH AMEIUCAN GINSENG ON
POSTPRANDIAL GLYCEMIA
- TAKEN TOGETHER WITH A GLUCOSE CHALLENGE -
POSTPRANDIAL GLYCEMIA
-TAKEN TOGETHER WITH A GLUCOSE CHALLENGE-
2.1 Introduction
The traditional method of consuming ginseng is to either to ingest the root or boil
the root in four volumes water until the level becomes one volume. It is nonnally taken on
an empty stomach [Personal communication, Li., 19961. The usual daily dose of Oriental
ginseng in Korea is 6.4 g per day [Personal communication, Park, 19961 . It has been
advised that since North Americans have generally large body size, a higher dose may be
required [Personal communication, Park, 19961. Furthemore, in TCM, the daily dose of
non-toxic herbs is usually in the range of 3 to 10 g, given as decoction or in pi11 or powder
forrn [Bensky and Gamble 19831.
2.2 Aim
The main objective of this study was to determine whether North American
ginseng or P. quznquefoIius can lower postprandial blood glucose when taken together
with a glucose challenge. Doses of 3 g, 6 g, and 9 g North American ginseng powder were
selected for this study in light of the Bensky and Garnble publication [1983].
2.3.1 Glucose challenge preparation and composition
The oral glucose drink (250 mL) was made by diluting 100 mL standardized
glucose solution (75 g glucose / 300 mL) (GIucodex, Rougier Inc.) with 150 rnL of water.
It consisted of 25 g available CHO. It was prepared fiesh on each study day.
2.3.2 Powder form of North American ginseng
The nutrient profile of the North American ginseng powder used in this study is
shown on Table 1.2. The powder was made by grinding the root hair taken from four to
five years old P. quniquefolius grown in Ontario or British Columbia, Canada (Atkins
Farm Ltd., Ontario; Chai-Na-Ta Corp., B .C.). The powder was encapsulated in gelatin
capsules, with each capsule containing either 490 mg or 500 mg of North American
ginseng powder. Al1 the ginseng powder capsules used in the study were generously
supplied by the two manufacturers (Atkins Farm Ltd., Ontario; Chai-Na-Ta Corp., B.C.)
and were obtained fiom the same manufacturers' batch.
2.3.3 Subiect recruitment and ~rofi le
Healthy non-smokers, with no previous history of diabetes or related metabolic
diseases, were recruited to participate in the study. None of them were not taking any
medications. Written consent (Appendix 1), approved by the Human Subjects Review
Committee at University of Toronto, was obtained fiom each subject aRer they had been
fully informed about the procedure and involvement required in the study.
28.6 + 3.1 years. The mean BMI was 24.0 f 1.1 kg/m2 and the mean fasting blood
glucose (FBG) was 4.7 f O. 1 mmol/L. Subject characteristics are Iisted in Table 2.1.
2.3.4 Experimental Desim
This study made use of a randomized, cross-over design in which each subject is
hisher own control. The oral glucose drink was prepared on each test day for the
subjects. Subjects were evaluated on six occasions. The control (glucose challenge) was
adiministered three times. The treatments consisted of three different doses of P.
quinquefolius powder taken together with the glucose drink as treatment, after a 10 to 12
hour-ovemight fast. Each of the subjects was randomized in an unique sequence of test
order as follows:
C- TX-C-Ty-Tz-C
(C = control, T = North American ginseng tests, x,y,z = different doses)
The control was administered three times in order to standardize intra-individual variation.
In addition, there was a washout period of at least two days between each test. Subjects
were asked to repeat a specific test if the result was significantly different (+ 2 SD) fiom
the group mean.
. - - ---. - - - - --- - - ----- F-- --.--i.-...-uii
Subjects were asked to corne to the Risk Factor Modification Centre at St.
Michael's Hospital afier a 10 to 12 hour-overnight fast. Finger-prick capillary blood
samples (250 yL) were taken at fasting and 15, 30, 45, 60, 90, and 120 minutes after
consumption of control or test. Before, collecting fasting blood, subjects were required to
be seated for 10 minutes and remain seated for the duration of the study. M e r the fasting
sample had been obtained, subjects were instructed to consume the glucose challenge
either with various doses of ginseng powder (3 g, 6 g, or 9 g) (T) or without ginseng for
control (C) steadily in 10 minutes. Finger-prick capillary blood samples were obtained
with Autolet Lancets (Owen Mudord Ltd., Woodstock, Oxon). Blood samples were
contained in pre-labeled fluoro-oxalate tubes and were kept frozen at - 2 0 ' ~ pior to
glucose analysis within 48 hours.
Characteristics Total (n=8) Males (n=5) Females (n=3)
Mean I SE Mean $: SE Mean f SE
(range) (range) (range)
Age (years) 28.6 + 3.1 30.4 15.0 25.7 f 1.7
(22.0 to 49.0) (23.0 to 49.0) (24.0 to 29.0)
BMI (kg/m2) 24.0 f: 1.1 24.9 I 1.4 22.4 f 1.6
(20.3 to 28.4) (20.6 to 28.4) (20.3 to 25.6)
FBG (mmoVL) 4.7 k 0.1 4.7 + O. 1 4.7 f 0.1
(4.4 to 5.0) (4.4 to 5.0) (4.6 to 4.8)
Capillary blood glucose concentrations were rneasured using an automatic analyzer
Stat Glucose Analyser, Yellow Springs Instruments, Yellow Spring, OH). This I
device utilizes the glucose oxidase technique [Shimizu et al., 19801. A standard glucose
solution, prepared by dissolving 1.8 g D-glucose in 1.0 L of distilled water, was used to
calibrate the glucose analyser. Al1 the sarnples were analysed only afier two successive
readings of the standard solution between 9.9 to 10.1 rnrnoi/L had been attained.
The glucose analyser is dependent on glucose oxidase to measure glucose
concentrations in blood. When a-D-glucose in blood samples makes contact with the
immobilized enzyme, glucose oxidase, it is rapidly oxidized producing hydrogen peroxide
@&O2). This H202 is, in turn, oxidized at the platinum anode, producing electrons. A
dynamic equilibrium is achieved when the rate of Hz02 production and the rate at which
hydrogen peroxide leaves the immobilized glucose oxidase layer are equivalent. This
equilibrium is indicated by a steady state response. The electron flow is linearly correlated
to the steady state of H z 0 2 concentration and therefore, also to the concentration of
glucose.
2.3.7 Statistical analvsis
Results were expressed as mean + standard error (SE), Incremental area under the
glucose curve (AUC), omitting area beneath the fasting level, was calculated geometrically
[Wolever et al., 19911. Statistical cornparisons of data at specific time points, glucose
peak, and AUC were done by repeated measures ANOVA. Newman-Keuls method was
- -
considered statistically significant if p < 0.05.
2.4 Results
2.4.1 Effects of North American einsen~ on postprandial ~lycemic
response when taken together with a ~lucose challenpe
There was no statistically significant diference at any of the time points, glucose
peak, nor AUC (Figures 2.1; 2.2; Table 2.2) among the control, and 3 g, 6 g, and 9 g
ginseng treatment. The mean + SE of al1 the time points and AUC are listed on Table 2.2.
-+ Control +- 3 g ginseng + 6 g ginseng -+ 9 g ginseng
I I I 1 I I 1 l 1 I I I i O 10 20 30 40 50 60 70 80 90 100 110 120 130
Time (minutes)
Figure 2.1 Effect of North American ginseng taken together with a glucose challenge on postprandial glycemic response (n = 8). Values are means I SE.
U Control €d3 g ginseng üiiïi 6 g ginseng
T EBd9 g ginseng
Control 3 g ginseng 6 g ginseng 9 g ginseng
Figure 2.2 lncremental area under glycernic response curve: North American ginseng taken toget her wit h a glucose challenge (n = 8). Values are means f SE.
Table 2.2 Blood glucose concentrations at specific tirne points, change in blood glucose peak and incremental areas under t
curve (AUC).
Ginseng BIood glucose concentrations (mmoVL) AUC (mmol.min/
A in O' 15' 30' 45' 60' 90' 120' Glucose Peak
Control 4.6 * 0.1 6.5 k 0.3 7.1 -t 0.3 6.4 f 0.5 5.3 + 0.4 4.4 * 0.2 4.3 f 0.1 2.5 Ic: 0.1 112.9 f 16
3 4.7k0.3 7.1 f 0.3 7.5k0.2 6.1 f 0.2 4.9'0.1 4.5'0.1 4.4'0.1 2.8k0.4 104.4 k 1 1
Values are mean f SE
The results indicated that there were no statistically significant differences in
postprandial blood glucose response between the treatments (3 g, 6 g and 9 g of North
American ginseng taken with a glucose challenge) and the control ( the glucose challenge
without any ginseng treatment).
However, one possible explanation might be that since ginseng did not interact with
the food, there was no change in the physical nature of food, such as changing food
viscosity as seen in the case of some soluble dietary fibres. The administration of ginseng
together with the glucose drink did not therefore, cause any changes in glucose absorption
rate. If ginseng caused any reduction in postprandial glycemia, it might be a result of
some other biological pathway. In other words, it might be certain pharmacological
phenornena rather than the physical alteration of food which entraps nutrients.
CHAPTER THREE
EFFECTS OF NORTH AMERICAN GINSENG ON
POSTPRANDIAL GLYCEMIA
- TAKEN PRIOR TO A GLUCOSE CHALLENGE -
- -- - - - .
POSTPRANDIAL GLYCEMIA
-TAKEN PRIOR TO A GLUCOSE CHALLENGE-
3.1 Introduction
In the previous experiment (Chapter 2), it was shown that when ginseng was
taken together with a glucose drink, it did not reduce postprandial blood glucose.
Therefore, it was hypothesized that ginseng might elicit its blood glucose lowering effects
through systemic pharmacological pathway other than physical nature of nutrients. The
traditional way of consurning ginseng is on empty stomach [Personal communication, Li,
19961. Perhaps, ginseng should be taken before the glucose challenge so that it can
'prime' or 'prepare' the system for physiological challenges.
3.2 Aim
The objective of this experiment was, therefore, to determine if North American
ginseng can reduce postprandial glycemia when it is administered before the glucose
challenge. The same oral glucose dnnk as Experiment 1 (Chapter 2) and 9 g of P.
qziinpefolius were used in this experiment. Finger-prick capillary blood samples were
collected at various time points and glucose concentrations were measured.
3.3 Materials and Methods
3.3.1 The com~ositions of glucose challenye and North American pinseng
Both the glucose drink and the ginseng powder used in this experiment were the
same as the ones used in the previous experiment (Sections 2.3.1; 2.3.2).
3.3.2 Subiect recruitment and ~rof i l e
The subject selection criteria were the same as Experiment 1 (Chapter 2). Written
consent (Appendix 1), approved by the Hurnans Subject Review Cornmittee, University
of Toronto, was submitted by each subject.
Seven subj ects (3 males + 4 females) were recruited. They were al1 normal at the
time of the study. Their mean age, BMI, and FBG were 31 f 4.2 years, 23 f 1.2 kg/m2,
and 4.5 f 0.1 rnrnoVL respectively. Subject characteristics are shown in Table 3.1.
3.3.3 Experirnental de-
This experiment employed a randomized, cross-over design. Thus, each subject
acted as hisher own control. There were a total of three separate tests, consisting of a
glucose challenge, ginseng control, and ginseng treatrnent (Figure 3.1). Subjects were
randomized to various sequences of test order. They were asked to perform each test
after a 10 to 12 hou-ovemight fast. The glucose drink was prepared fiesh on each test
day .
I I I 1 I
-80 O 15 30 45 60 90 min
'r T
Glucose ControI 300 mL water 250 mL glucose drink
Ginseng + Glucose 300 mL water 250 mL glucose drink + 9 g ginseng
Ginseng Control 300 mL water 250 mL water + 9 g ginseng
Figure 3.1 Experimental design
3.3.4 Studv ~rocedure and blood sam~Ie collection
Subjects were requested to attend the Risk Factor Modification Centre at St.
Michae17s Hospital following a 10 to 12 hour-overnight fast. Upon arrival, subjects were
asked to remain seated throughout the duration of the study. Fasting finger-prick capillary
blood sample was taken at the beginning using Autolet Lancets (Owen Mumford Ltd.,
Woodstock, Oxon), followed by an ingestion of 9 g North American ginseng powder
contained in gelatin capsules with 250 to 400 rnL of water. After 80 minutes, another
finger-prick blood sample was obtained. A glucose challenge, consisted of 25 g glucose,
was then consumed. Further finger-prick blood samples were collected at 15, 30, 45, 60,
and 90 minutes f i e r the glucose challenge.
For glucose and ginseng controls, finger-prick blood samples were also collected
at the same specified time points. For the glucose control, 300 rnL of water was given
without any ginseng pnor to the glucose challenge. For the ginseng control, 250 rnL of
water was ingested instead of the glucose drink following the consumption of 9 g ginseng
powder. This protocol provided possible control for postprandial glycemic response
attributed to North Arnencan ginseng powder.
Al1 blood samples were collected in pre-labeled fluoro-oxalate tubes. They were
kept fiozen at -20 OC before glucose analysis within 48 hours.
Table 3.1 Subject Profile
Characteristics Total (n=7) Males (n=3) Females (n=4)
Mean f SE Mean f SE Mean f SE
(range) (range) (range)
Age (years) 31.0 f 4.2 33.7 + 7.9 29.0 + 5.3
(23.0 to 49.0) (23.0 to 49.0) (23.0 to 45.0)
BMI (kg/m2) 24.0 f 1.1 25.1 + 1.7 23.1 + 1.7
(20.1 to 28.4) (23.4 to 28.4) (20.3 to 28.0)
FBG (mmoi/L) 4.5 + O. 1 4.6 1 O. 1 4.5 f O. 1
(4.3 to 4.9) (4.3 to 4.9) (4.2 to 4.8)
3.3-5 Blood plucose analvsis
Capillary blood samples were measured using the same procedure and equipment
as the previous experiment (Section 2.3.6).
3.3.6 Statistical analvsis
Results were expressed as mean + SE. Statistical comparisons of data at specific
time points, glucose peak, and AUC were done by one-way ANOVA with repeated
measures. Newman-Keuls method was used as a post test to compare individual means
for multiple comparisons. Differences were considered to be statistically significantly
different if p < 0.05.
3.4 Results
3.4.1 Effects of North American gins en^ on ~ostprandial blood
glucose resDonse when taken before the glucose challenpe
Ginseng + glucose resulted in a 30.3 + 6.4% decrease (p < 0.01) in AUC from that
of the glucose alone (Figure 3.1). Both the AUC of the glucose alone and ginseng +
glucose were substantially larger (p < 0.001) than that of the ginseng alone (Table 3.2). In
fact, the AUC of ginseng alone was deterrnined at 1.6 + 1.4 mmol.min/L, while the AUC
of the glucose alone and ginseng + glucose were respectively found to be 120.0 + 9.4 and
82.3 + 8.2 mmol.minL (Figure 3.1).
North American ginseng taken at 80 minutes prior to the glucose load produced a
significantly lower (p c0.05) blood glucose concentration on the postprandial glycemic
Table 3.2). Blood glucose concentrations at 15, 30, 45 and 60 minutes on the ginseng
control curve were also significantly lower (p< 0.05) than that on both the glucose control
and ginseng treatment (Table 3.2).
Ginseng alone
E Glucose alone mm Ginseng + Glucose
Figure 3.2 lncremental area under glycemic response curve: North Arnerican gineng taken prior to a glucose challenge (n = 7). Values are means * SE. Means with different letters differ significantly (p < 0.05) by ANOVA.
Table 3.2 Blood glucose concentrations at specific time points, change in blood glucose peak,
and incremental areas under the curve (AUC)
Blood glucose concentrations (mmoVL) AUC (mmol.min/l
A in -80' O' 15' 30' 45' 60' 90' Glucose Peak
a a a a a a Ginsengalone 4.5f0.1 4.520.1 4.4f0.1 4.410.1 4.410.2 4.3f0.1 4.4f0.1 0.2M.1 1.6f 1.4
b b b b b b Glucose alone 4.5 I 0.1 4.5 + 0.1 5.9 I 0.3 7.7 k 0.3 6.9k0.2 5.0 f 0.3 4.2 kO.l 3.3M.2 120.0 I 9.4
Ginseng + b c c b c c Glucose 4.5 IO.l 4.6 IO.l 6.2 I 0.1 7.1 f 0.2 5.8 f0.4 4.8 2 0.3 4.2 f 0.1 2.4H.2 82.3 f 8.1
Values are mean ' SE. Means with different letter superscnpts within a column differ significantly (p<0.05) as determined by ANOV followed by Neuman-Keuls method.
9- Blood Glucose Concentration + Ginseng (mmow -A- Glucose
4-
Time (minutes)
Figure 3.3 Effect of North American ginseng on postprandid blood glucose when taken prior to a glucose challenge (n = 7). Values are means SE. Means with different letters verticalIy differ significantly (p < 0.05) by ANOVA.
3.5 Discussion
The results indicated that 9 g P. quinquefolius powder when administered 80
minutes pior to glucose challenge reduced postprandial blood glucose peak at 30 minutes
and decreased AUC by 31.4%. AUC on the ginseng control curve was found to be
negligible which indicated that ginseng powder alone did not contribute significantly to the
postprandial rise in blood glucose. As a result, AUC on the ginseng treatment curve did
not need to be adjusted.
This finding showed that North Amencan ginseng taken pior to glucose load was
effective in lowering post-meal blood glucose in normal humans, which might indicate that
it was a pharmacological effect. However, it remained uncertain whether there was an
effective time and dose of administering ginseng powder .
CHAPTER FOUR
OPTIMAL TIME AND DOSE OF
NORTH AMERICAN GINSENG ADMINISTRATION
NORTH AMERICAN GINSENG ADMINISTRATION
4.1 Introduction
P. quinquefolius has been demonstrated to lower postprandial blood glucose
response when taken prior to a glucose load (Chapter 3). This finding is the first time in
which North Arnerican ginseng is shown to have a postprandial hypoglycemic response in
healthy humans. This effect, however, is not seen when administered together with the
glucose drink (Chapter 2). Thus, the purpose of this phase is to determine the optimal
time and dose of taking North Arnerican ginseng powder.
4.2 Aim
The main purpose of this study was to find the optimal dose and time of taking
North Amencan ginseng powder such that the maximal postprandial hypoglycemic effect
can be elicited. Doses of 3 g, 6 g, and 9 g of P. quinquefolius were selected as
Experiment 1 for the same reason (Chapter 2). Each of these doses will be taken at 40,
80, and 120 minutes before the glucose challenge.
4.3 Materials and Methods
4.3.1 The com~osition of standard meal and North American ginseng
Both the standard meal and the ginseng powder used in this study was the same as
the ones used in the previous experiments (Sections 2.3.1 ; 2.3.2).
The requirements for selecting subjects for this phase were identical to the ones in
Experiments 1 and 2 (Chapters 2; 3). Al1 subjects were asked to return a signed consent
form (Appendix 1) that had been approved by the Humans Subject Review Cornmittee of
University of Toronto.
There were altogether six subjects (4 males + 2 females) participated in this study.
They were al1 healthy non-srnokers at the time of the study. They had an average age of
36.7 f 5.4 years, a mean BMI of 25.1 & 1.3 kg/m2, and a mean FBG of 4.4 + 0.1 mrnol/L.
Subject characteristics are shown in Table 4.1.
4.3.3 Experimental d e s i ~ n
This study employed a randomized, cross-over design in which each subject is his
or her own control. There were a total of twelve tests, comprising three different doses of
North American ginseng (3 g, 6 g, and 9 g), each of which was taken at three different
times (-120, -80, and -40) prior to meal, and three glucose controls. There was a washout
period of at least two days. Al1 subjects were randomized to an unique sequence of test
order as follows:
where C = control, T = North Arnerican ginseng test,
and 1 ,. .,9 = different dose and time
They were also asked to perform each test afier a 10 to 12 hour overnight fast. The oral
glucose drink was prepared on each test day.
4.3.4 Studv ~rocedure and blood sarnple collection
Subjects were asked to corne to the Risk Factor Modification Centre, St.
Michael's Hospital following a 10 to 12 hour overnight fast. Throughout the duration of
the study, al1 participants were asked to remain seated. A fasting blood sarnple was
collected before any ingestion using Autolet Lancets (Owen Mumford Ltd., Woodstock,
Oxon). For the control (C), subjects were asked to consume a glucose drink, which
consisted of 25 g glucose, and collect blood at 15, 30, 45, 60, and 90 minutes. For
ginseng powder tests (T), either 3 g, 6 g, or 9 g North American ginseng powder was
taken with 300 mL water. After either 40, 80, or 120 minutes, another finger-prick blood
sample was obtained. A glucose drink, containing 25 g glucose, was then consumed.
Further capillary blood samples were collected at 15, 30, 45, 60, and 90 minutes after
ingestion of the glucose challenge. Al1 blood samples were contained in pre-labeled
fluoro-oxalate tubes. They were kept fiozen at -20 OC before glucose analysis within 48
hours.
4.3.5 Blood plucose analvsis
Finger-prick capillary blood samples were measured using the same procedure and
equipment described in Chapter 2 (Section 2.2.6).
4.3.6 Statistical Analvsis
Results were presented as mean + SE. Statistical comparisons of AUC for al1
three doses and time of ginseng administration were done by two-way ANOVA (Table
4.2). One-way ANOVA with repeated measures was employed to further compare the
effectiveness of each given dose ingested at each specified time with that of the control.
Comparisons of data at specific time points for each dose with glucose control were done
by one-way ANOVA. Newman-Keuls post test was used to compare individual means for
multiple comparisons following both two-way ANOVA and one-way ANOVA.
Differences were statistically significant if p < 0.05.
4.4 Results
When 3 g and 6 g of North Arnerican ginseng powder were taken at either 40 (p <
0.05) or 80 minutes (p < 0.05) pnor to the glucose drink, it resulted in a lower AUC as
compared to glucose alone. Lower AUC's were also seen when 9 g of P. quinquefolius
powder was ingested at either 40 (p < 0.01), 80 minutes (p < 0.01), or 120 minutes (p <
0.05) before the glucose challenge. (Figure 4.1). However, AUC's for al1 three doses of
ginseng powder taken at 40, 80, and 120 minutes before glucose challenge were not
significantly different (Table 4.2). In addition, niether time, dose nor the interaction
between time and dose appeared to contribute to the overall reduction of postprandial
glycemia.
ginseng powder at either 40, 80, or 120 minutes before the glucose load are show in
Figure 4.2. Although there was no significant difference, it appeared that 3 g, 6 g, and 9 g
of ginseng powder ingested 40 minutes prior to glucose load tended to have greater
reductions in postprandial hypoglycernic response (Figure 4.2).
Lower blood glucose concentrations at 45 minutes were found when 3 g, 6 g, 9 g
ginseng were taken at 40 and 80 minutes before glucose challenge when compared to
glucose alone (Figures 4.3; 4.4; 4.5).
Table 4.1 Subject Profile.
Characteris tics Total (n=6) Males (n=4) Females (n=2)
Mean f SE Mean + SE Profile
(range) (range)
Age (years) 36.7 f 5.4 36.8 f 7.1 25.0 and 48.0
(23.0 to 49.0) (23.0 to 49.0)
BMI (kg/m2) 25.1 f 1.3 25.3 f 1.1 20.2 and 28.9
(20.2 to 28.9) (23.6 to 28.4)
FBG (mmoVL) 4.4 f 0.1 4.4 +_ 0.1 4.2 and 4.8
(4.4 to 4.9) (4.4 to 4.9)
Glucose alone
ml -40 minutes H -80 minutes
ab O -120 minutes b
b r a b b
T
Figure 4.1 Incremental area under glycemic response curve: 3 g, 6 g, 9 g of North American ginseng powder taken at -40, -80, -120 minutes before a glucose challenge (n=6). Values are means f SE. Means with different letters differ significantly (p < 0.05) by ANOVA.
American ginseng powder administration tirne, dose, and tirne-dose interaction.
Source p-value
Dose 1073.2 2 536.6 0.58 0.5613
Dose-Time Interaction 182.9 4 45.7 0.05 0.9952
Time of North American ginseng powder administration (minutes)
Figure 4.2 Percent reduction in AUC wi th different ti me and dose of North Arnerican ginseng powder administration (n=6). Values are means f SE.
+ Glucose alone + -40 minutes + -80 minutes + - 120 minutes
,O 4- rn
3 1 I 1 I 1 1 I 1 1 I
O 10 I
20 30 40 50 60 70 80 90 1 O0
Time (minutes)
Figure 4.3 Effects of 3 g North American ginseng on postprandial blood glucose when taken at 40,80,120 minutes prior to a glucose challenge (n = 6). Values are means SE. Means with different letters vertically differ significantly (p < 0.05).
+ Glucose donc + -40 minutes + -80 mi nutes -e -120 mi nutes
40 50 60
Ti me (mi nutes)
Figure 4.4 Effects of6 g North American ginseng on postprandial blood glucose when taken at 40,80,120 minutes prior to a glucose challenge (n = 6). Values are means * SE. Means with different letters vertically diffcr significantly (p < 0.05).
+ Glucose alone -t -40 mi nutes + -80 minutes + -120 minutes
Time (mi nutes)
Figure 4 5 Effects of 9 g North American ginseng on postprandial blood glucose when taken at 40,80,120 mi nutes prior to a glucose challenge (n = 6). Values are means i SE. Means w ith different letters vertical1 y differ significantl y (p < 0.05).
These results confirmed the previous finding (Chapter 3) that 9 g of North
American ginseng powder administered 80 minutes before a glucose challenge resulted in
a decreased postprandial blood glucose response (p < 0.01) as shown by a lower AUC
compared to glucose alone (Figure 4.1).
North American ginseng powder (3 g, 6 g, 9 g) taken either at 40 or 80 minutes
before glucose challenge lowered postprandial glycemic response by decreasing blood
glucose concentrations at 45 minutes after the glucose load (Figures 4.3; 4.4; 4.5).
Neither time nor the interaction between time and dose appeared to play a role in reducing
postprandial glycemic response (Table 4.2). However, a trend was be seen (Figure 4.1) in
that North Anerican ginseng powder (3 g, 6 g, 9 g) taken closer to the glucose challenge
time appeared to cause a greater decrease in AUC. This level of reduction seemed to
gradually diminish as ginseng was ingested further fiom glucose ingestion time. A greater
sample size would be necessary to confirm this trend.
Since there was no significant difference in percent reduction of AUC among the
three dosages taken at three difference times, an optimal time and dose of administering
North Amencan ginseng powder could not be determined. This might suggest that lower
doses of ginseng need to be further tested. However, it could be concluded that lower
doses of ginseng powder (3 g and 6 g) elicited postprandial hypoglycemic responses in
normal healthy humans when they were taken shortly before the glucose challenge (40 and
80 minutes). A high dose of North American ginseng powder (9 g) produced lower
" - - - - - - - - - - - - - - - - - - - -- .. -- '-'--" -- - Y"V" Y . .W.. a
period of tirne pior to the glucose challenge (40, 80, 120 minutes) (Figure 4.1).
CHAPTER FIVE
GENERAL DISCUSSION
AND
CONCLUSION
5. GENERGL DISCUSSION AND CONCLUSION
5.1 General discussion and future research
Previous studies with animals and humans have suggested that Oriental ginseng
may be useful in treating diabetes [Kimura et al., 1981a; 1981b; Kimura and Suimki,
1982; Waki et al., 1982; Konno et al., 1984; Yokozawa et al., 1984; Konno et al., 1985;
Oshima et al., 1985; Wang et al., 1985; Yokozawa et al., 1985; Sotaniemi et al., 19951.
These findings seem to support the traditional claim that Oriental ginseng is an effective
treatment for diabetes (Section 1.2.1 S). Chemical analyses of Oriental and North
American ginseng have shown that they both contain many reputedly active components
and have very sirnilar nutrient profiles (Tables 1 . l ; 1.2). Consequently, it was
hypothesized in this study that North American ginseng also possesses similar
hypoglycemic effects as its Asian cousin.
Recent findings by Cui et al. [1996] and Hasegawa et al. [1996] demonstrated that
ginseng components could be absorbed. This group was able to detect GS fiagments in
blood, urine, and feces in human athletes who consumed ginseng preparation orally,
suggesting that ginseng saponin fragments were absorbed afier oraI ingestion. In addition,
animal studies in which ginseng components and fractions extracted fiom Oriental ginseng
root were injected i.p. into both chemically-induced and genetic diabetic rats, as well as
normal rats had shown to have hypoglycemic properties [Konno et al., 1984; Konno et al.,
1985; Oshima et al., 19851. Since i.p. injection in animals can be extrapolated to oral
that oral administration of ginseng may have blood glucose lowering effects in humans.
The present study demonstrated that oral ingestion of North American ginseng
with a glucose challenge does not cause any reduction in postprandial blood glucose
response (Chapter Z), while consumption of P. quinquefolius p io r to the glucose
challenge has considerable postprandial hypoglycernic response (Chapters 3; 4). It
appears that since ginseng does not alter the physical nature of food, for example the
viscosity of certain soluble fibres, no change in postprandial blood glucose results when
ginseng is taken together with the glucose load. This suggests that the reduction in blood
glucose response after the glucose dnnk may due to a pharmacological efEect rather than
a physical modification of food causing a decrease in absorption rate in the small intestine.
However, there remain uncertainties about the optimal dose, and whether the time of
ingestion prior to the glucose challenge is a contributing factor to reducing postprandial
glycemia. Nevertheless, this study is the first to demonstrate that North American ginseng
powder when taken orally produces a lower postprandial glycemic response in healthy
individuals. In addition, it also seems to suggest that the eRective dose of North American
ginseng powder rnay be lower than 3 g.
Although decreases in blood glucose and insulin rise after ingestion of
carbohydrate-rich meals sometimes indicate delay of absorption rate [Jenkins et al., 19951,
it remains unclear whether such absorption delay is the result of reduced gastric emptying
or hormonal changes. In addition, plasma insulin which is helpfùl in fiirther understanding
the mechanism by which North American ginseng causes postprandial hypoglycemia was
a , > . . - . - - - ----, -'- - '- "' " " a l ....a au.
human trial for fbture studies on the application of P. qt~inquefoliz~s in the management of
NIDDM, future clinical trials should aim at elucidating the mechanism of ginseng's action
by first determining whether ginseng reduces glucose absorption by slowing ga~tric
emptying or by acting on the endocrine system.
Several factors need to be considered when accounting for a delay in gastric
emptying. Each gelatin capsule in this study contained either 490 mg or 500 mg ginseng
powder. Therefore, the doses of 3 g, 6 g, and 9 g of ginseng used in this study (Section
2.3.2) was consistent of 7, 13, and 19 capsules respectively. As a result, the bulk of the
material may have caused the delay in postprandial glucose absorption by slowing gastric
emptying. However, there was no significant difference between 3 g, 6 g, and 9 g ginseng
powder in lowering postprandial blood glucose despite their differences in material
bulkiness. (Figure 4.1). As a consequence, the material bulkiness of the capsules is
unlikely to be an important factor. In order to firther illustrate this in fbture experiments,
xylose can be given together with ginseng to compare its urinary levels before and after
each test to that of controls with no ginseng. A reduced urinary xylose output tends to
correspond with a dower mouth-to-cecum transit time [knkins et al., 19781, and thereby
indicates delayed gastric emptying. Thus, if there is no change in unnary xylose levels
between ginseng-treated and untreated meals, there is no slowing of gastric emptying
associated with North Arnerican ginseng. Lactulose can also be used to determine
whether gastric transit time is delayed [Jenkins et al., 19781 by comparing breath gases
from lactulose control, glucose alone with lactulose and ginseng treatment with lactulose.
of North American ginseng. Although the exact mechanism is not understood, it is
postulated that it is related to its effects on the hypothalamus during stresshl situations
(Section 1.2.6). As a consequence, it remains unclear how ginseng elicits its
pharrnacological effects. The use of radio-labeled glucose may be usefùl in understanding
the mechanism by which North American ginseng improves overall glucose both normal
and NIDDM individuals. In additiion, fùture studies may also need to measure other
blood parameters in addition to glucose. For example, insulin, free fatty acids, IHDL,
LDL, triglycerides, cortisol, glucagon, and catecholamines measurements can al1 shed light
in understanding the mechanism.
There are many different species of Panmc known to exkt (Table 1.5). Besides,
there are other plants which have sirnilar appearance as Panmc species but are botanically
different. Furthemore, some of the ginseng components Vary in quantities depending on
the year of growth (Table 1.7) which may affect potency of the ginseng. It has been
illustrated that certain GS are of highest quantity at four or five year of growth [Zhang et
al., 19801. As a consequence, it is important for future that the particular variety of
ginseng chosen is, in fact, P. quinquefolius and that they are selected from the same
manufacturer batch of four to five year-old roots. It may also be necessary to assay
certain ginseng components and determine the nutrient profile of any new supplies of
ginseng so that ginseng material can be better standardized. For more consistent ginseng
materials, standardized ginseng extracts rnay also be useful in ensuring potency.
and diabetic humans, a similar protocol can be used to test the effectiveness of other
Panax species with similar year of growth in the lowering of postprandial glycemia. In
addition, the optimal time and dose of administration of each species and their possible
mechanism of action can also be determined. As a result, in the fùture it may be possible
to rank different Panax species of ginseng in order of effectiveness. Long-term human
trials with NIDDM patients can also give light to the possibility of including North
Arnerican ginseng powder in overall NIDDM management.
5.2 General conclusion
The overall objective was to determine if North American ginseng powder could
lower postprandial blood glucose response. North American ginseng taken together with
a glucose challenge did not lower postprandial glycemic response, while ginseng taken at
any given dose with given time prior to the glucose load greatly reduced postprandial
blood glucose response. This indicated that ginseng might elicit its postprandial blood
glucose lowering effect by certain pharmacological pathways, instead of altenng the
physical nature of food substances to entrap nutrients.
The results of this study also suggested that P. quinquefolius (3 g, 6 g, 9 g)
lowered postprandial glycemia when it was taken either at 40 or 80 minutes prior to the
glucose challenge. In addition, at a high dose of 9 g ginseng taken at 120 minutes pior to
the glucose load also produced a similar reduction in postprandial blood glucose. This
suggests that the dose levels selected in this study may be too high to detect the
ginseng administration by developing dose curves fiom O to 3 g and at deterimining the
optimal time of ginseng administration.
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APPENDIX
CONSENT FORM
INTRODUCTION
Ginseng is a man-shaped root indigenous to Asia, North America and Russia. Its value in promoting overall body health has long been recognized by the Chinese as precious and renowned. In fact, they have been using ginseng for more than 5,000 years. Ginseng has traditionafly been thought to prolong fife, boost energy, elevate sex drive and soothe base emotions. Over the years, many other conditions, including diabetes, have been reported to be alleviated by the constant consumption of ginseng. However, these claims are generally based upon anecdotal evidence. Therefore, the purpose of this study is to investigate the efficacy of North American ginseng in normal humans and to determine the time and dose of administration.
PROCEDURES
Phase 1:
This phase consists of 12 individual tests in which each test lasts for a maximum of 3.5 hours. In each test, I will be asked to come to the Clinical Nutrition and Risk Factor Modification Centre, 61 Queen Street East after a 10-12 hour-ovemight fast. 1 will give seven capillary blood samples in each test. Each sample requires 3-5 drops (1/4 tablespoon) of blood.
When 1 reach the Clinic, 1 will give a fasting finger prick capillary blood sample. Then, 1 will ingest either 3, 6, or 9 g (7, 13, 18 capsules) of North American ginseng powder contained in gelatin capsules 1 120, 240, or 360 mg (4, 8, or 12 capsules) of North American ginseng extract contained in soR gel capsules with 250-400 mL water in 10 minutes. After either 40, 80, or 120 minutes, 1 will give yet another finger prick capillary blood sample.
1 will then take an oral orange glucose drink consisting of 100 mL Glucodex@ @M 00509965) and 150 mL water. This drink contains 25 g glucose. Once again, 1 will collect finger prick capillary blood at 15, 30, 45, 60 and 90 minutes afier consuming the glucose drink. The blood samples will be analyzed for glucose levels,
This phase consists of 2 individual tests in which each test lasts for a maximum of 2.5 hours. In each test, 1 will be asked to corne to the Clinical Nutrition and Risk Factor Modification Centre, 61 Queen Street East after a 10-12 hour-overnight fast. 1 will give 8 venous blood samples in each test. Each sample requires 30 mL (2 tablespoons) of blood.
When 1 reach the Clinic, 1 will give a fasting venous blood sample. I will consume either 3, 6, or 9 g (7, 2 3, or 18 capsules) of North American ginseng powder contained in gelatin capsules / 120, 240, or 360 mg (4, 8, or 12 capsules) of North h e r i c a n ginseng extract contained in soft gel capsules with 250-400 mL water in 10 minutes with 250 - 400 mL water.
M e r either 40, 80, or 120 minutes, 1 will give another venous blood sample. 1 will then drink an oral orange glucose drink contain 100 mL GlucodexB @IN 00509965) and 150 mL water. This dnnk has 25 g glucose.
Venous blood sample will be taken at 15, 30, 45, 60, 90, and 120 minutes afier the ingestion of the orange drink. The venous blood samples will be analyzed for hormones and lipids.
RISKS
There are no known risks from ginseng powder and extract. However, minor discornfort is expected when the needle is inserted into my vein. Bniising may occur when the needle is removed but this can be prevent by keeping pressure on the site for 3-5 minutes after the removal of the needle. If bruising occurs, it will go away in 2-3 days.
BENEFITS
1 may expect to benefit from this study in the following ways: my blood sugar, blood lipids, blood hormones may improve. 1 will receive the benefits of evaluation of symptoms and general health discussions with the doctor and help in finding additional treatment if needed. 1 wiI1 have a chance to contribute to a study which may be of benefit to people in the fùture.
CONFIDENTIALITY
The results from the study will be confidential. My results will not be shown to anyone, unless required by law, with my written permission. My results will be sent to my physician if 1 wish.
1 understand that the study investigator may stop my being in the study at any time without my consent. My participation may be discontinued if the study investigator judges that this is in my best interest or if 1 fail to comply to study procedures.
QUALIFICATIONS
1 understand 1 cannot be in this study if 1 abuse alcohol or drugs, of if 1 have a senous illness which is not under control. 1 am above the age of 18 years.
CONSENT
1 have read this consent form, have had al1 my questions about the study answered, and believe 1 know what will happen to me if 1 agree to be a part of the study. 1 understand that 1 may reach Dr. Vladimir Vuksan at (416) 867-7450 if 1 have further questions pertaining to the study.
1 may quit at any tirne. If 1 decide not to participate or quit, 1 will not be penalized and wiI1 not give up any benefits of which 1 had before entering the study. If 1 decide not to participate or quit, 1 will notiQ the study investigator. 1 have received a copy of this consent form.
Volunteer's ................ .................................................. Signature: ........... ................ Date:
Investigator's .................................................. ..................................................... Name: Date:
Investigator's . . . .................................................. Signature : .................................... .. Date:
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