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Journal of the American College of Nutrition, Vol. 23, No. 3, 248-258 (2004)
Published by the American College of Nutrition

Original Research

Decreasing, Null and Increasing Effects of Eight Popular Types of Ginseng on Acute Postprandial Glycemic Indices in Healthy Humans: The Role of Ginsenosides

John L. Sievenpiper, PhD, John T. Arnason, PhD, Lawrence A. Leiter, MD and Vladimir Vuksan, PhD

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto (J.L.S., L.A.L., V.V.), CANADA
Department of Biology, Faculty of Science, University of Ottawa, Ottawa (J.T.A.), CANADA

Address reprint requests to: Vladimir Vuksan, PhD, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, #6 138-61 Queen Street East, Toronto, Ontario, M5C 2T2, CANADA. v.vuksan{at}utoronto.ca


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Background: It is unclear whether other ginseng sources can replicate the glycemic-lowering efficacy observed previously with American ginseng and whether ginsenosides are mediators. We assessed the effect of eight popular ginseng types on postprandial plasma glucose (PG) and insulin (PI) indices, linking effects to ginsenoside profiles.

Methods: Using a double-blind, randomized, multiple-crossover design, 12 healthy participants (gender: 6M:6F, age: 34 ± 3 y, BMI: 25.8 ± 1.2 kg/m2) received 10 3g treatments: American, American-wild, Asian, Asian-red, Vietnamese-wild, Siberian, Japanese-rhizome, and Sanchi ginsengs and two placebos. Each treatment was given 40-minutes before a 75g-oral-glucose-tolerance-test (75g-OGTT) with blood drawn at –40, 0, 15, 30, 45, 60, 90, 120-minutes. HPLC-UV analysis quantified seven principal ginsenosides.

Results: Two-factor analysis showed the main effects of ginseng-type and time were significant for PG and PI, with an interaction for PG (p < 0.05). Subsequent one-factor analysis showed an effect of ginseng-type on 90-min-PG and 90-min-PI (p < 0.05). This was reflected in effects on peak-PG, area under the curve (AUC)-PG and AUC-PI (p < 0.05). But the effect on 90-min-PI and AUC-PI were significant (p < 0.05) only in overweight participants (BMI > 25 kg/m2, n = 6). Planned comparisons with placebo showed a tendency for American ginseng and Vietnamese ginseng to lower 90-min-PG (p < 0.06), while Asian ginseng raised peak-PG and AUC-PG, American-wild ginseng raised 120-min-PG, and Siberian ginseng raised 90-min-PG, 120-min-PG, and AUC-PG (p < 0.05). Stepwise-multiple-regression assessed the protopanaxadiol:protopanaxatriol (PPD:PPT)-ginsenoside ratio as the sole predictor (p < 0.05) for 90-min-PG (ß = –0.43, r2 = 0.072), AUC-PG (ß = –0.25, r2 = 0.06), 90-min-PI (ß = –0.26, r2 = 0.065), AUC-PI (ß = –0.20, r2 = 0.04).

Conclusions: Ginseng has variable glycemic effects, in which the PPD:PPT-ginsenoside ratio might be involved. But the low variance explained suggests the involvement of other unmeasured ginsenoside or non-ginsenoside components.

Key words: complementary and alternative medicine, ginseng, ginsenosides, acute, postprandial, OGTT, glucose, insulin secretion, insulin sensitivity


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Physicians now indicate that more than 75% of their patients use complementary and alternative medicine (CAM) therapies that include herbs [1]. These patterns of use have occurred in the absence of adequate regulatory standards, patient disclosures to physicians and physician education. A recent systematic review of 42 randomized and 16 nonrandomized clinical trials of herbs and dietary supplements used for glycemic control in diabetes also reported that although shown to be safe, there is insufficient evidence to make conclusions about their efficacy [2]. This lack of a foundation to support disease treatment claims has prompted a unified call from the editors of the major medical journals for more randomized controlled trials of herbs [3–8].

Despite the best evidence for efficacy in diabetes supporting the further evaluation of ginseng using this rigorous approach [2], variable effects complicate generalizability. We have shown that, while one batch of American ginseng demonstrated reproducible glycemic lowering efficacy in a series of dosing and timing response studies in people with and without type 2 diabetes [9–13], a second batch with a depressed ginsenoside (glycosidal saponin) profile was ineffective [14] and Asian ginseng with marked species-specific inversions in its ginsenoside profile produced no effect or increased glycemia in combined dose response studies [15]. The question remains whether other ginseng types with a wide range in their ginsenoside composition are able to replicate the glycemia lowering we observed previously with American ginseng and whether ginsensoides are mediators. To investigate these possibilities, we compared the acute effects of single doses of eight of the most popular ginseng types on postprandial glycemic indices, linking differences in effects to differences in their ginsenoside profiles.


   METHODS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Participants
Fourteen healthy nondiabetic participants without previously diagnosed glycemia were recruited from faculty and students at the University of Toronto and hospital advertisements. Informed written consent was obtained from the participants before beginning the study, which was approved by the research ethics board at St Michael’s Hospital. Twelve (gender: 6 males, 6 females, age: 34 ± 3 y [range: 18–53 years], BMI: 25.8 ± 1.2 kg/m2 [range: 18.8–33.9 kg/m2], body fat: 15.8 ± 2.2% for males [range: 8.1–23.4%], 27.5 ± 3.6% for females [range: 17.5–38.4%]) of the 14 participants completed the study. One participant withdrew due to a time conflict, and a second was excluded due to subsequently diagnosed impaired glucose tolerance by World Health Organization (WHO) criteria [16]. The remainder of the participants had their normal glucose tolerance status confirmed by applying the WHO criteria [16] to their 2h plasma glucose (2h-PG) values during the two 75g-oral glucose tolerance tests (75g-OGTTs) administered with placebo in the study. Of the 12 participants that completed the study, 10 were of Caucasian descent and two were of Asian descent.

Design
The study used a randomized, double-blind, multiple-crossover, double-placebo controlled design. Each participant received 10 single-dose treatments in random order: 3g of ground whole root of American (Panax quinquefolius L.), American-wild (wild Panax quinquefolius L), Asian (Panax ginseng C.A. Meyer), Asian-red (steam treated Panax ginseng C.A. Meyer), Vietnamese-wild (Panax vietnemensis), Siberian (Eleutherococcus senticosus), Japanese-rhizome (Panax Japonicus C.A. Meyer), and Sanchi (Panax notoginseng [Burk.] F.H. Chen) ginsengs and two identical placebos. The two placebos were meaned and treated as one for all comparisons. The reason for this redundancy was to increase the probability of obtaining a truer control for comparisons with the eight ginseng types.

Treatments
The eight ginseng and two placebo treatments were derived from several sources. The Korean Ginseng Cooperative Federation, Korean Institute of Ginseng and Tobacco Research, Seoul, Korea supplied the Asian and Asian-red ginseng batches. Chai-Na-Ta Corp (Langley, BC) provided the American ginseng batch. Professor Kazou Yamasaki from Hiroshima University provided the Japanese-rhizome, Vietnamese-wild, and Sanchi ginseng batches. The American-wild ginseng was purchased from Mary Ginseng House (Toronto, ON) and the nonpanax Siberian ginseng (Nature’s Way Canada, Newmarket, ON) was purchased from a local health food store. All batches were received as ground dried root powder with the exception of the Japanese-rhizome, Vietnamese-wild, Sanchi, and American-wild ginseng batches that were received as dried whole root. These latter four batches were ground at Mary Ginseng House (Toronto, ON). After grinding, all treatments were encapsulated in identical gel capsules at a weight of 500 mg. The placebo consisted of encapsulated corn-flour provided by Chai-Na-Ta Corp (Langley, BC). Both placebo treatments were identical and indistinguishable from the eight ginseng treatments. To ensure stability, all treatments were stored in a cool, dry, dark location over the course of the study and used within 12 months of receipt. Attempts were made to match the energy and carbohydrate content of the placebo with the ginseng treatments.

Protocol
The protocol followed the WHO guidelines for the administration of a 75g-OGTT [16]. Participants attended the Risk Factor Modification Centre at St. Michael’s hospital following a 10- to 12-hour overnight fast. A minimum of three days separated each visit to minimize carry-over effects. Each participant was instructed to maintain the same dietary and exercise patterns the evening before each test and consume a minimum of 150g of carbohydrate each day over the three days prior to the test. To ensure compliance, participants completed a questionnaire detailing pre-session information about their diet and lifestyle patterns and submitted to measurements of their body weight and total body fat, assessed by infrared-interactance using a FUTREX-5000® (FUTREX Inc., Gaithersburg, MD). Upon commencement of the OGTT, participants had a catheter inserted into a forearm vein that was secured by tape and kept patent by saline. From this device a fasting 7 mL-blood sample was obtained in a plasma tube (–40-min sample). Treatment capsules were then administered with exactly 300 mL of tap water. The start of the capsules signaled the start of running time. Participants had another blood sample drawn after 40-min (0-min sample). This was followed by consumption of the 75g oral glucose load (75g-Glucodex®, Technilab, Quebec, Canada) over exactly 5-min. This consumption time was verified by digital timers. Additional blood samples were drawn using the same technique at 15, 30, 45, 60, 90 and 120-min after the start of the challenge. To assure that the venous samples were sufficiently arterialized, participants kept their collection arms wrapped in heating pads for the duration of the protocol. Adverse symptom monitoring during each clinic visit and in the intervening washout days (≥3 days) was assessed by subjective 7-point bipolar visual analogue scales.

Ginseng Analyses
The ginsenoside profile of the ginseng and placebo capsules was measured using standard techniques. The ginsenosides are composed principally of a family of steroids called dammarane-type triterpene glycosides with either (20S)-protopanaxadiol (PPD) or (20S)-protopanaxatriol (PPT) as the aglycone. The four principal PPD ginsenosides (Rb1, Rb2, Rc, Rd) and three principal PPT ginsenosides (Rg1, Re, Rf) were analyzed using HPLC-UV techniques developed for the American Botanical Council (ABC) Ginseng Evaluation Program [17]. A Beckman HPLC system chromatograph with a reverse-phase Beckman ultrasphere C-18, 5 µm octadecylsilane, 250 x 4.6 mm column was used. The mobile phase consisted of de-ionized water and acetonitrile. The flow rate was 1.3 mL/min. UV detection was done using a module 168 diode-array detector set at 203 nm. The ginsenoside standards for Rg1 and Re were provided by Dr. H. Fong University of Illinois and the Rf, Rb1, Rc, Rb2, Rd standards were provided by Indofine Chemical Co., Somerville NJ. PPD and PPT ginsenoside subtotals, total ginsenosides, and various ginsenoside ratios (PPD:PPT, Rb1:Rg1, Rb2:Rc, Rg1:Re) were derived from individual analyzed ginsenoside concentrations.

Plasma Glucose and Insulin Analyses
All samples were separated by centrifuge (1240 x g for 15-min at 4°C) and the plasma immediately frozen at –20°C pending analysis. Analyses of glucose concentration of each sample were done by the glucose oxidase method [18] and the insulin concentration, by double antibody radioimmunoassay [19], at the Banting and Best Diabetes Centre Core Laboratory, Toronto, Canada. By these techniques, the intra-assay coefficient of variation (CV) for glucose was 1.7% at a mean glucose concentration of 5.3 mmol/L and 0.72% at a mean glucose concentration of 33.2 mmol/L, while the intra-assay CV for insulin was 5.8%, 5.4% and 5.7% at mean insulin concentrations of 83.10, 234.26 and 467.09 pmol/L, respectively.

Statistical Analyses
Various indices of glucose and insulin regulation were derived from PG and PI during the OGTT. Incremental PG and PI curves, calculated as the change from baseline (–40-min), were plotted and the positive incremental area under the curve (AUC) was calculated [20]. Incremental values were used to control for baseline differences between the treatments. Absolute values for peak-PG and peak-PI independent of time and 2h-PG were also assessed. Other derived indices included the whole body insulin sensitivity index (OGTT-ISI) [21] and the early insulin secretion index, {Delta}PI30–0/{Delta}PG30–0 [22]. Both were calculated using absolute PG and PI values in derived equations for the OGTT. The OGTT-ISI was calculated using fasting PG (FPG) and PI (FPI) with mean OGTT outcome, according to the formula [21]: 10 000 divided by the square root of ([FPG x FPI] x [mean-PG x mean-PI]), where PG is expressed in mg/dL and PI in µU/mL. PG values in mmol/L were divided by 0.0551 to obtain mg/dL and PI values in pmol/L were divided by 6 to obtain µU/mL for this last formula. The early insulin secretion index, {Delta}PI30–0/{Delta}PG30–0, was calculated as the change in PI from 0 min to 30 min divided by the change in PG over the same period [22]. All of these derived data were meaned for the 2 placebos. Statistical analyses were then performed using the Number Cruncher Statistical System (NCSS) 2000 software (NCSS statistical software, Kaysville, Utah). The data were tested for normality. Non-normally distributed data (OGTT-ISI) were log-transformed for statistical analyses. Two-way repeated measures ANOVA assessed the interactive and independent effects of ginseng-type (Asian, American, American-wild, Sanchi, Siberian, Japanese-rhizome, Asian-red, Vietnamese-wild, placebo) and protocol time (–40, 0, 15, 30, 45, 60, 90, 120-min) on incremental PG and PI. Two-way repeated measures ANOVA also assessed the interactive and independent effects of ginseng-type and overweight (BMI > 25 kg/m2) on incremental PG and PI. If the interactions were significant, then the they were explored with one-way repeated measures ANOVAs. This same statistic assessed differences in peak-PG, 2h-PG, AUC-PG, peak-PI, AUC-PI, AUC-PI, OGTT-ISI, and {Delta}PI30–0/{Delta}PG30–0, as well as differences in subjective ratings of symptoms for both the clinical testing and washout periods. A priori planned pairwise comparisons were done using non-orthogonal contrasts between placebo and each ginseng type to determine efficacy relative to placebo. Stepwise-multiple regression analyses assessed the independent ginsenoside predictors of the PG and PI indices found to be significant in categorical analyses among the eight ginseng types. Each stepwise regression model contained all seven analyzed individual ginsenosides and the derived PPD and PPT subtotals, total ginsenosides, and ratios for the eight ginseng types. All results were expressed as mean ± SEM and considered significant at p < 0.05 for differences and associations and p < 0.1 for interactions.


   RESULTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
The study protocol for all 10 treatments was followed safely and without difficulty by the participants. A minimum of 150g of carbohydrate was consumed over the three days prior to each test. Intra-subject variation in baseline anthropometry (weight – CV = 0.9 ± 0.1%, BF – CV = 8.6 ± 1.4%) and FPG (CV = 6.6 ± 0.47%) and FPI (CV = 21.6 ± 2.2%) were within expected limits across visits. The participants consumed all placebo and ginseng treatment capsules in the self-standardized amount of time and the 75g Glucodex® oral glucose load in the allotted 5 min for each test (range: 5:00 min–5:06 min). There were also no differences among the placebo and ginseng treatments in reported symptoms that included bloating, belching, nausea, dizziness, headache, diarrhea, flatulence, polyuria, insomnia, anxiety, numbness, light-headedness, drowsiness, sore-throat, or vomiting during the clinic visits or intervening washout periods.

Effect of Ginseng Type on PG and PI Indices
The effect of ginseng type (Table 1) and time on 75g-OGTT derived PG and PI indices were assessed. Two-way repeated measures ANOVA showed that the main effects of ginseng type (p = 0.030, p = 0.045) and time (p < 0.0001, p < 0.00001) on incremental PG and PI respectively were significant, with the interaction between treatment and time significant for PG (p = 0.046). This interaction was explored with one-way repeated measures ANOVA, in which the eight types of ginseng and the mean of the two placebos were compared at each level of time (–40, 0, 15, 30, 45, 60, 90, 120-min). There was a significant effect of ginseng type on 90-min-PG (p = 0.00086) and 90-min-PI (p = 0.014). This was reflected in a significant effect on absolute peak-PG (p = 0.046) and incremental AUC-PG (p = 0.0086) and AUC-PI (p = 0.034) but not absolute 2h-PG (p = 0.18), peak-PI (p = 0.22), OGTT-ISI (0.23), or {Delta}PI30–0/{Delta}PG30–0 (p = 0.74). These effects of ginseng type on 90-min-PI and AUC-PI were dependent upon the weight status of the participants (p < 0.10 for the interaction). One-way ANOVAs done separately in the normal weight (BMI < 25 kg/m2, n = 6) and overweight (BMI > 25 kg/m2, n = 6) participants showed that the significant effect of ginseng type on these PI indices was only true for the overweight participants (p < 0.05).


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  		Table 1. Effect of Ginseng Type on 75g-OGTT Plasma Glucose and Insulin Indices

 
Relative Efficacy of Eight Ginseng Types
The significant effect of ginseng type were explored by a priori planned pairwise comparisons assessing efficacy of each ginseng type relative to the mean of the two placebos. Nonorthognal contrasts for PG showed that there was a tendency for American ginseng (p = 0.052) and Vietnamese ginseng (p = 0.062) to lower incremental 90-min-PG (p = 0.052), while Asian ginseng raised absolute peak-PG (p = 0.022) and incremental AUC-PG (p = 0.0046), American-wild ginseng raised incremental 120-min-PG (p = 0.028) and absolute 2h-PG (p = 0.020), and Siberian ginseng raised incremental 90-min-PG (p = 0.037), 120-min-PG (p = 0.037), and AUC-PG (p < 0.05) compared with placebo (Fig. 1). Nonorthognal contrasts for PI showed that Asian ginseng raised 0-min-PI (p = 0.044) and there was a nonsignificant tendency for Vietnamese-wild ginseng to decrease 60-min-PI (p = 0.095), 90-min-PI (p = 0.10), and AUC-PI (p = 0.082) and increase OGTT-ISI (p = 0.079) compared with placebo (Fig. 2). One-way ANOVAs done separately in the normal weight (BMI < 25 kg/m2, n = 6) and overweight (BMI > 25 kg/m2, n = 6) participants again showed that the relative efficacy of ginseng type compared with placebo on the PI indices was dependent on weight status of the participants. Vietnamese-wild ginseng significantly decreased 90-min-PI (p = 0.039) and AUC-PI (p = 0.040) compared with placebo in the overweight participants only.



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  		Fig. 1. Differential effects of eight types of ginseng on postprandial plasma glucose: The line plots and bars in the array represent the incremental change and area under the curve (AUC) for the mean of two identical placebos (•) or one of eight of the most popular ginseng types, Sanchi, Siberian, American, Asian, Asian-red, Japanese-rhizome, American-wild, or Vietnamese [wild] ginseng, ({circ}) administered at a dose of 3 g 40-min before a 75g-OGTT in 12 healthy nondiabetic subjects (sex: 6m:6f, age: 34 ± 3 y, BMI: 25.8 ± 1.2 kg/m2). Asterisks indicate that points or bars for ginseng are significantly different from placebo (p < 0.05, one-way repeated measures ANOVA with non-orthogonal contrasts). AUC data were logarithmically transformed for statistical analyses to normalize their distribution. Data are mean ± SEM.

 


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  		Fig. 2. Differential effects of eight types of ginseng on postprandial plasma insulin: The line plots and bars in the array represent the incremental change and area under the curve (AUC) for the mean of two identical placebos (•) or one of eight of the most popular ginseng types, Sanchi, Siberian, American, Asian, Asian-red, Japanese-rhizome, American-wild, or Vietnamese [wild] ginseng, ({circ}) administered at a dose of 3 g 40-min before a 75g-OGTT in 12 healthy nondiabetic subjects (sex: 6m:6f, age: 34 ± 3 y, BMI: 25.8 ± 1.2 kg/m2). Asterisks indicate that points or bars for ginseng are significantly different from placebo (p < 0.05, one-way repeated measures ANOVA with non-orthogonal contrasts). AUC data were logarithmically transformed for statistical analyses to normalize their distribution. Data are mean ± SEM.

 
Ginsenoside Composition
The ginsenoside profiles were compared among the 8 types of ginseng and placebo (Table 2) and, where possible, evaluated according to the criteria for their authentication. The composition of each type of ginseng was found to be consistent with the criteria for authentic ginseng of the type each represented. Several examples are applicable. First, a Rb1:Rg1 ratio <3 is indicative of Panax ginseng C.A. Meyer and Panax notoginseng [Burk.] F.H. Chen while a Rb1:Rg1 ratio >3 is indicative of Panax quinquefolius L [23–25]. Batches of the former two species (Asian, Asian-red, and Sanchi ginsengs) and the latter species (American and American-wild ginsengs) met their respective criteria. Second, ratios of Rg1:Re and Rb2:Rc > 1 [26] are both indicative of Panax ginseng C.A. Meyer, while the opposite is true for Panax quinquefolius L. [23–26]. The batches of Asian and Asian-red ginseng met these criteria for Panax ginseng C.A. Meyer and American and American-wild ginsengs met these criteria for Panax quinquefolius L. Third, the presence of Rf is distinctive for Panax ginseng C.A. Meyer [23–27]. Only the batches of this species (Asian ginseng and Asian-red ginseng) contained this ginsenoside. Finally, the absence of all ginsenosides is distinctive for Eleutherococcus senticosus [24,28]. The Siberian ginseng was devoid of all ginsenosides. These interspecies differences contributed to marked differences between the eight different types of ginseng. There was a large difference between the ginseng type with the lowest ginsenoside content or ratio versus the ginseng type with the highest content or ratio. It ranged from ninefold comparing Asian to American-wild ginseng for Re to 50-fold comparing Vietnamese-wild to American-wild ginseng for Rb2. Similarly, it ranged from twofold comparing Asian to Japanese-rhizome ginseng for the PPD:PPT ratio to 54-fold comparing American to Sanchi ginseng for the Rg1:Re ratio.


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  		Table 2. Ginsenoside Profiles of the 8 Common Types of Ginseng and Placebo

 
Relationship between PG and PI Indices and Ginsenoside Composition
The wide range in ginsenoside content and ratios among the eight different types of ginseng were linked to differences in PG and PI indices found to be significant in categorical analyses (Table 3). Stepwise multiple regression models assessed the independent predictors of these effects. The stepwise regression models that included all of the individual ginsenosides or their subtotals, total, or ratios selected Rd and the PPD:PPT ginsenoside ratio for the 90-min-PG multiple regression model, and the PPD:PPT ginsenoside ratio for the AUC-PG, 90-min-PI, and AUC-PI multiple regression models. No ginsenoside parameters were selected for the peak-PG, 2h-PG, or peak-PI multiple regression models. The multiple regression analyses assessed the sole independent predictor of the effects on 90-min-PG, AUC-PG, 90-min-PI, AUC-PI as the PPD:PPT ginsenoside ratio (p ≤ 0.05). The direction of the relationship was negative in each case, such that the higher the PPD:PPT ratio the lower PG and PI indices. The variance in PG and PI indices explained by the differences in this ratio was from only 4% to 7%.


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  		Table 3. Stepwise-Multiple Regression Analysis of the Independent Ginsenoside Predictors of Plasma Glucose (PG) and Insulin (PI) Indices

 

   DISCUSSION
 
The present study achieved a wide range in ginsenoside profiles among the eight common commercial types of ginseng. This coincided with an equally wide range in PG effects. Differential and sometimes contradictory acute PG effects were observed among the different types of ginseng when given at a 3g dose 40-min before a 75g-OGTT. Cultivated American ginseng significantly decreased, while Asian, Siberian, and American-wild ginseng significantly increased indices of acute postprandial PG compared with placebo. Asian ginseng significantly increased acute preprandial (0-min) PI, while Vietnamese-wild ginseng decreased acute postprandial PI compared with placebo significantly only in those subjects who were overweight (BMI > 25 kg/m2). All other types of ginseng demonstrated null effects on these indices.

These variable findings are not unexpected. The divergent findings for American and Asian ginseng on indices of PG and PI regulation are consistent with previous findings from our clinic. We noticed that 6g of our original efficacious batch of American ginseng lowered the plasma glucose response to a 75g-OGTT significantly (p < 0.05) in eight healthy nondiabetic subjects using the same intravenous protocol [13,14]. This is in addition to the reductions we reported with the same batch in an earlier series of dosing (1–9g) and timing (120-min to 0-min before oral glucose) response studies, following capillary blood glucose protocols using a 25g-OGTT protocol [10–12]. In contrast, we observed in two previous dose escalation studies that the mean of doses from 1–9g of the same batch of Asian ginseng from the present study significantly increased plasma glucose at the diagnostically and therapeutically relevant 2hPG [15].

Differential effects of ginseng have also been described elsewhere in the literature. Although different panax species such as Asian [29–36], American, and Sanchi [35] ginseng and nonpanax species of ginseng such as Siberian ginseng [35] have repeatedly demonstrated hypoglycemic effects in vitro and in animal models, the magnitude and direction of their effects can be quite variable. For example, glycemia was reduced from 2% to 15% by Shiu-Chi red and Sanchi ginseng, respectively, while increased by 12% by US grown American ginseng in one acute study in the rat [35]. Other studies have shown differential effects across different batches within the same species. For example the Asian ginseng root extract, G115, at a dose of 50 mg/kg for three months increased glycemia by greater than twofold in the resting and exercised rat [37], while an aqueous extract of Asian ginseng root over a 20-fold dose range for 5–10 days showed null effects in the streptozotocin diabetic rat [38]. In contrast, an extract of Asian ginseng whole root at 1000 mg/kg for 15–16 days and Asian ginseng berries at 150 mg/kg for 12 days decreased glycemia by 35% in the streptozotocin diabetic rat [39] and the ob/ob mouse [40], respectively. Different root fractions have also shown differential effects. While the water-soluble, DPG series fractions of Asian ginseng significantly lowered acute glycemia in alloxan diabetic mice, the fat-soluble fractions, D-8151, D-81513, had null effects and the fat-soluble fraction, D-81516, had increasing effects. A specific water extracted fraction, DPG-4, containing ginsenosides identified as Rb and Rc also had increasing effects on acute blood glucose [36]. Taken together, variability in glycemic effects has been shown among different species, preparations, plant parts and root fractions.

Reasons for this variability are unclear. A compelling possibility is that ginsenosides might be involved. Similar differential effects have been seen among isolated ginsenosides. Total ginsenosides and ginsenosides Rb1 and Rb2 at a dose of 10 mg/day for three days decreased serum glucose significantly by >65% in the streptozotocin diabetic rat [41]. In another study, ginsenoside Rb2 at the same dose for six days decreased glycemia by a smaller 30% in the streptozotocin diabetic rat [42]. Ginsenoside Re at doses from 5–20 mg/kg for 12 days decreased glycemia maximally by 25% in the ob/ob mouse [40]. In an in vitro study, PPT, (20R)-PPD, Rg1, Rc, Rd, Re, Rf, Rg2, Rh1, Rb1 and Rb2 ginsenosides at doses from 0.01–10 µM showed stimulative effects of 109% to 129% of control on 2-Deoxy-D-[23H]glucose (2-DG) uptake by GLUT-1 in isolated sheep erythrocytes [43]. In contrast, total ginsenosides and ginsenoside Rg1 at a dose of 10 mg/day for three days increased glycemia nonsignificantly in the normal rat [41]. Ginsenoside Rg3 at a dose of 10 µM showed inhibitory effects and Rd, Ro and Rh2 at all doses from 0.01–10 µM showed null effects on 2-Deoxy-D-[23H]glucose (2-DG) uptake by GLUT-1 in isolated sheep erythrocytes [43]. Total PPT ginsenosides at doses from 10–100 µg were observed to inhibit [14C]-{alpha}-mean glucose uptake by SGLT-1 in a dose dependent manner in cultured rabbit renal proximal tubular cells [44]. These decreasing, null, and increasing effects of different ginsenosides might be driving differences between batches, species, plant parts and preparations.

This possible primary influence of ginsenosides is supported by our present findings. The HPLC-UV analyses demonstrated that each of the eight ginseng types had a distinct ginsenoside profile. The stepwise multiple regression analysis linked these distinct profiles to the differential PG and PI responses. It showed that the sole independent predictor of four of the seven indices of PG and PI regulation was the PPD:PPT ratio, such that the higher the ratio, the lower were PG and PI indices. A comparison between the profile of our original efficacious batch of American ginseng [9–13] and the present batch of American ginseng also shows that the PPD:PPT ratio is similar (2.44 versus 2.13 for a difference of <13%). These findings are consistent with stimulatory effects on glucose transport and PG lowering described above for the PPD ginsenosides, total PPD, Rb1, and Rb2 and the inhibitory effects described above for the PPT ginsenosides, total PPT and Rg1.

Ginsenosides, nevertheless, do not appear to exert a strong influence in the present study. The proportion of the changes in the four of seven indices of PG and PI regulation explained by the changes in the PPD:PPT ratio was a maximum of 7%, suggesting the involvement of other components. It is possible that the >20 other known ginsenosides [28] that were not measured in the present study are participating in the effects independently or interactively. Alternatively, non-saponin compounds could be involved. These might include the peptidoglycans: panaxans A-U from Asian ginseng [45–47], eleutherans A-G from Siberian ginseng [48], and quinquefolans A-C from American ginseng [49]. All three classes of peptidoglycans have shown hypoglycemic effects [45–49] with varying degrees of potency when administered as intraperintoneal injections in both normal and alloxan induced hyperglycemic mice. Minerals shown to decrease glycemia such as chromium, vanadium and magnesium [2] must also be considered. Involvement of other components may explain why Siberian ginseng exhibited a PG increasing effect in the absence of ginsenosides. Their involvement may also explain why the cultivated and wild American ginsengs could have such disparate PG effects while having a nearly identical PPD:PPT ratio (2.13 versus 2.11).

Biological variability in the response to ginseng might also be another important source of variability. Our observation that the effect of ginseng type on PI indices was dependent upon the weight status of the participants, such that Vietnamese ginseng significantly lowered PI indices compared with placebo in the overweight (BMI > 25 kg/m2) participants only, suggests that there might be phenotypic differences in the response to ginseng. Overweight clusters with insulin resistance as part of the metabolic syndrome [50]. In this regard, the overweight participants had a higher degree of insulin resistance compared with their normal weight counterparts, as indicated by an ~27% lower OGTT-ISI score (6.83 ± 0.8 vs. 9.34 ± 0.53, p < 0.05 for a between groups Student’s t test). It is possible that those with this syndrome might derive the greatest benefit. This might be interpreted as consistent with our previous observation that the effect of our original efficacious batch of American ginseng was most robust in the subjects with type 2 diabetes, in whom overweight and insulin resistance were present. It was in this group that the American ginseng lowered acute post-OGTT glycemia after all times of administration, whereas in the nondiabetic subjects, the ginseng had to be given a minimum of 40-min before the OGTT to achieve reductions [9–13]. Although it is speculative to suggest that the difference in response was owing to overweight and insulin resistance, this combination and, more broadly, the metabolic syndrome might contribute to some of the glycemic variability following ginseng administration.

In conclusion, not all types of ginseng batches, species and preparations are equal in their effects on glycemic and insulinemic regulation. Decreasing, null and increasing effects were seen across different types of ginseng secondary to the variability in their composition. These effects however are not predicted wholly by differences in their seven principal ginsenosides. Although the results of the present study point to the PPD:PPT ratio as playing a significant independent role, this ratio explains only a small fraction of the effects on PG and PI regulation. The remaining unexplained variability compromises generalizability. Although our findings confirm the hypoglycemic effects of a new batch of American ginseng and the hyperglycemic effects of the same batch of Asian ginseng used in our previous studies, these opposite effects cannot be ascribed to all batches of these species. The same is true for the hyperglycemic effects seen with Siberian ginseng and wild American ginseng. Although each of the eight types of ginseng studied was shown to be authentic by its ginsenoside composition, we do not know whether the batches studied are representative. We also do not know whether reproducing the measured ginsenoside profiles will lead to the same results. The implication is that, without the ability to tie specific profiles to specific indications, generalizability of efficacy and safety is questionable, even where there is standardization of ginsenoside content. Consumers and practitioners alike should be warned of this uncertainty, while researchers must design studies to identify the specific aspects of its composition that drive the variability in humans. In this last case, phenotypic differences in the response to ginseng related to overweight or insulin resistance that may be a source of biological variability between people needs also to be explored further in studies with better power. Our clinic is presently undertaking investigations to address these issues.


   ACKNOWLEDGMENTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
The funding for this study was provided by a Grant for Applied Research and Education from the Canadian Diabetes Association. JLS was in receipt of an Ontario Graduate Scholarship during the conduct of this work. The placebo and ginseng batches used in the study were generously donated by The Korean Ginseng Cooperative Federation, Korean Institute of Ginseng and Tobacco, Seoul, Korea (Asian, Asian-red, and Sanchi ginsengs), Chai-Na-Ta Corp, Langlay, BC (American ginseng and placebo), and Professor Kazou Yamasaki from Hiroshima University (Japanese-rhizome and Vietnamese-wild ginsengs). We thank Denise Lamure for excellent technical assistance in the handling and processing of blood samples and Jeremy Quan at the Banting and Best Diabetes Centre Core Laboratory for prompt and expert analyses.

Partial findings from this study were presented at the Federation of American Societies for Experimental Biology (FASEB) conference held in New Orleans, LA from April 20–24, 2002 [51] and the 20th International Symposium on Diabetes and Nutrition held in Samos, Greece from June 27–29, 2002 [52].


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Dr. Vuksan has received research and travel funding from Chai-Na-Ta Corp., Langley, BC; MuscleTech Research and Development Incorporated, Mississauga, ON; the Ontario Ginseng Growers Association, Simcoe, ON; Ginseng Growers of Canada, Simcoe, ON; Ontario Ministry of Agriculture, Toronto, ON, the Korean Ministry of Agriculture, Soeul, South Korea; and BioSapogen Inc, Seoul, South Korea

Received June 20, 2003. Accepted November 11, 2003.


   REFERENCES
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 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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