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Original Research |
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto and Clinical Nutrition and Risk Factor Modification Centre (V.V., M.P.S., J.L.S., V.Y.Y.K., E.W., U.B.-Z., T.F., A.L.J., L.A.L., R.G.J., Z.X.), St. Michael’s Hospital, Toronto, CANADA
Division of Metabolism and Endocrinology (V.V., L.A.L., R.G.J.), St. Michael’s Hospital, Toronto, 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. E-mail: v.vuksan{at}utoronto.ca
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Ten nondiabetic individuals (6M:4F; mean ± STD: age = 41 ± 13 years, BMI = 24.8 ± 3.5 kg/m2, FBG = 4.5 ± 0.1mmolL-1) on 12 separate occasions, randomly received 0 (placebo), 3, 6 or 9g of ground AG root at 40, 80, or 120 minutes before a 25g oral glucose challenge. Capillary blood glucose was measured prior to ingestion of AG or placebo capsules and at 0, 15, 30, 45, 60 and 90 minutes from start of challenge.
Results: Compared with the placebo, 3, 6 and 9g of AG reduced (p<0.05) postprandial incremental glucose at 30, 45 and 60 minutes; also, 3 and 9g of AG did so at 90 minutes. At 60 minutes, 9g of AG reduced incremental postprandial glucose relative to 3g of AG (p<0.05). All AG doses reduced (p<0.05) area under the incremental glucose curve (3g, 26.6%; 6g, 29.3%; 9g, 38.5%). AG taken at different times did not have an additional influence on postprandial glycemia.
Conclusions: In nondiabetic individuals, 3, 6 or 9g of AG taken 40, 80 or 120 minutes before a glucose challenge similarly improved glucose tolerance.
Key words: American ginseng, Panax quinquefolius L., glucose tolerance, nondiabetic, dose, time of administration
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Blood glucose levels can be reduced through dietary means, including dietary fibre [8,9], feeding pattern [10] and meal volume [11]. Also, inclusion of lente carbohydrates, such as beans, lentils and pasta as opposed to highly refined grains will slow the absorption of glucose from a diet [12]. Two recent prospective studies showed that men and women consuming a diet in the lowest glycemic load quintile were 36% less likely to develop diabetes than those consuming one in the highest [13, 14]. In addition, a low glycemic index diet may reduce the risk of developing CVD [15]. Benefits analogous to these may also be achieved with dietary supplements [16] and herbs [17,18] that can attenuate blood glucose rises.
In the case of herbs, ginseng, traditionally used as a tonic in Oriental medicine, has demonstrated a hypoglycemic effect in numerous animal experiments [19–21]. This effect has been confirmed in both long- and short-term clinical studies [22,23]. Sontaniemi et al. showed that daily consumption of 200mg of ginseng of an unspecified source reduced HbA1c in individuals with type 2 diabetes [22]. As well, we recently demonstrated that 3g American Ginseng (AG; Panax quinquefolius L.) given 40 minutes before a 25g glucose challenge improves postprandial glucose tolerance in individuals with and without type 2 diabetes by approximately 20% [23]. We now hypothesize that further improvements in glucose tolerance will be achieved with escalation of AG dose and administration time in nondiabetic individuals.
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METHODS |
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Study Treatments
Ontario-grown, ground root of AG was encapsulated in 500mg gelatin capsules and used for the study. The placebo consisted of corn flour (similar in carbohydrate and caloric content to the ginseng treatment). Both ginseng and placebo capsules were identical in appearance. All ginseng and placebo capsules came from the same lot.
In order to elucidate the combined effect of AG dose and time of administration on postprandial glycemia, all participants randomly received 0 (placebo), 3, 6, or 9g of AG at 40, 80, or 120 minutes before a 25g oral glucose challenge (100mL of a 300mL 75g Glucodex® solution, Technilab, Quebec, Canada diluted with 200mL of tap water). Thus, each subject underwent 12 separate tests.
Study Design
Participants attended the Clinical Nutrition and Risk Factor Modification Centre at St. Michael’s hospital on 12 separate mornings following a 10 to 12 hour overnight fast. A minimum of three days separated each visit to avoid carry-over effects. Each participant was instructed to maintain the same dietary pattern the evening before and the same lifestyle patterns the evening and morning before each test [24].
At the commencement of each test (immediately prior to the ingestion of placebo or AG which was 40, 80 or 120 minutes before consumption of the glucose challenge), the participants had a fasting finger-prick capillary blood sample taken (approximately 250 µL), using a Monoejector Lancet device (Owen Mumford Ltd., Woodstock, Oxon, England). Subsequently, one of the 12 treatments was administered with 300mL of tap water, in random order using a single blind design. After the specified time had passed (40, 80 or 120 minutes), the participants had another blood sample drawn (0 minutes) and then consumed the glucose challenge over exactly a five-minute period. Additional finger-prick blood samples were obtained 15, 30, 45, 60, and 90 minutes after the start of the glucose challenge. The participants remained sedentary throughout the test.
Blood Glucose Analysis
Blood samples were collected in fluoride oxalate coated tubes, immediately stored at -20°C and analyzed within three days of collection. The concentration of glucose in each sample was determined with the glucose oxidase method employing the YSI 2300 Stat glucose/L-lactate analyzer, Model 115 (Yellow Springs, Ohio, U.S.). We measured the interassay coefficient of variance of this method for two sample pools to be 3.1% (n=143, 4.11±0.14mmolL-1) and 2.1% (n=117, 16.47±0.33mmolL-1).
Statistical Analyses
Blood glucose concentration was expressed as incremental blood glucose and incremental area under the blood glucose curve (AUC). The incremental blood glucose curves were plotted as the change in incremental blood glucose over time and the positive incremental AUC was calculated geometrically for each participant, (starting from 0 time) ignoring areas below the 0 time value. Incremental blood glucose concentrations were used so as to control for baseline/fasting differences between the treatments [25]. Repeated measures two-way analysis of variance (ANOVA) assessed interactive and independent effects of dose (0, 3, 6 or 9g) and time (40, 80 and 120 minutes) on blood glucose at each time point (15, 30, 45, 60, 90, 120 minutes), adjusted for multiple pairwise comparisons with the Newman-Keuls procedure. This same statistic assessed interactive and independent effects of dose (0, 3, 6 or 9g) and time (40, 80 and 120 minutes) on AUC. All results were expressed as mean±SEM and were considered statistically significant at the 5% significance level.
Energy and Nutrient Analysis
Energy and nutrient measurements of the American ginseng and placebo used in the present study were measured using standard techniques. Energy, fat, protein and carbohydrate content were measured by Chai-Na-Ta corporation using Official Analytical Chemists methods for macronutrients [26].
Ginsenoside Analysis
The content of various ginsenosides (Rg1, Re, Rf, Rb1, Rc, Rb2, and Rd), which are dammarane saponin molecules found among Panax species, was determined in the laboratory of Dr. John T. Arnason at the Department of Biology, Faculty of Science, University of Ottawa, Ontario, Canada, using high-performance liquid chromatography (HPLC) analyses, a method similar to the one developed for the American Botanical Council Ginseng Evaluation Program [27]. A Beckham HPLC system with a reverse-phase Beckham ultrasphere C-18, 5µm octadecylsilane, 250 x 4.6mm column was employed for analyses. The ginsenoside standards used for comparison were provided by two sources. Rg1 and Re were provided by Dr. H. Fong University of Illinois and Rf, Rb1, Rc, Rb2, Rd were provided by Indofine Chemical Co., Somerville NJ.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Time 0 Blood Glucose versus Fasting Blood Glucose
At time 0 the blood glucose concentration did not differ from the fasting blood glucose concentration for any dose-time modality of AG.
Effect of Dose
Fig. 1 shows the effect of different AG doses (0, 3, 6 or 9g) on incremental changes in glucose concentration (A) and blood glucose AUC (B) in nondiabetic individuals following a 25g glucose challenge (independent of administration time). The glucose concentrations for each time interval in Fig. 1A and the AUC values for each AG dose in Fig. 1B represent the mean of the three administration times (40, 80 and 120 minutes) for the individual AG doses.
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The overall pattern of reduced glycemic response to the 25-g oral glucose challenge with AG supplementation compared to placebo was further supported by a reduction in AUC with all AG doses (26.6% with 3g, 29.3% with 6g, 38.5% with 9g; p<0.05; Fig. 1B).
Effect of Time
Fig. 2 shows the effect of different times of AG administration (40, 80 or 120 minutes before the glucose challenge) on (A) incremental changes in blood glucose concentration and (B) blood glucose AUC in nondiabetic individuals following a 25g oral glucose challenge (independent of dose of AG). The glucose concentrations for each time interval in Fig. 2A and the AUC values for each pre-glucose administration time in Fig. 2B represent the mean of the four AG doses (0, 3, 6 and 9g) for the individual administration times. No significant differences were found between the individual AG administration times.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The results of this study coincided with our previous finding that 3g of AG consumed 40 minutes before a 25g glucose challenge improves glucose tolerance in normoglycemic individuals [23]. However, the current results contradicted our study hypothesis, such that no further enhancement of glucose tolerance occurred with escalating AG doses above 3g, to 6 and 9g, and/or administering them earlier than 40 minutes, at 80 and 120 minutes before the glucose challenge. The reasons for this may be multifaceted. A possibility is that maximum physiological response to AG occurs when 3g (or less) are consumed 40 minutes before a meal. Thus, although larger AG doses taken earlier may result in higher blood-AG concentrations, there is no further stimulation of hypoglycemic activity. Additionally, AG doses greater than 3g may show improved efficacy with a larger glucose meal and/or in individuals with a lower capacity for glucose tolerance (i.e those with IGT or diabetes). Overall, for convenience in normoglycemic individuals, 3g AG consumed 40 minutes before a 25g glucose challenge may be the most appropriate dose-time modality for improvement of glucose tolerance, as tested in the current study.
The rationale for our study design extends from Oriental medical practice, which recommends that herbals be taken at a daily dose of approximately 10g, with 3g as the minimum dose [28]. Thus, we used 3, 6 and 9g of AG to acquire a more comprehensive understanding of AG’s hypoglycemic effect within its traditionally recommended dosing range. Oriental medicine also stipulates that herbs be taken between meals, not in combination with them. We therefore administered AG at different times prior to the glucose meal to test this additional mode on glucose tolerance.
An additional reason for not raising the dose of AG above 9g was to prevent possible side effects from ginseng that have been previously reported [29]. Siegel [29] described the ginseng abuse syndrome—a group of symptoms arising from excessive ginseng intake. His report indicated that individuals consuming 15g of ginseng per day experienced depersonalization and confusion [29]. However, it should be noted that Siegel’s report did not describe the study participants, include a control group or analyze the ingested ginseng for authentication. Nonetheless, we decided to take precautions but also remained aware of Chandler’s [30] indication that excessive ginseng consumption involves very low risk to the user.
Users of ginseng should also be aware that there is no current standardization of ginseng products. Ginseng quality is represented by the content and profile of ginsenosides—dammarane saponins that are primarily characterized by (i) a four trans-ring rigid steroid skeleton and (ii) sugar moieties [31,32]. The steroid component can be divided into two major classes, 20(S)-protopanaxadiol and 20(S)-protopanaxatriol, and attached to the steroid are sugar residues. The type, number and site of attachment of the sugars impart structural and functional variation among the ginsenosides [31]. To date approximately 30 ginsenosides have been identified [33], and nine of these (Rb1, Rb2, Rc Rd, Rg1, Re, Rf, F11 and Ro) are often used in comparing ginseng species, samples or products.
The content and profile of ginsenosides differ between ginseng species and can differ among raw samples and commercial products of the same species [32,33,34,35,36]. For example, in Panax quinquefolius L., F11, a high Rc/Rb2 ratio and the absence of Rf are unique characteristics, whereas the presence of Rf is a distinctive feature of Panax ginseng C.A. Meyer [32,33,34]. These differences probably arise from genetic variations. The ginsenoside analysis in the current paper showed a high Rc/Rb2 ratio and the absence of Rf, circumstances which are consistent with the Panax quinquefolius L. literature (F11 was not determined in this study). When considering samples of a single ginseng species, the location of growth, the growing environment (wild or cultivated), the age of the roots, the different parts of the plant and the extraction methods will affect quantitative differences in total and individual ginsenosides [32,35]. As for commercial products, Cui [36] reported that root powder and extract preparations of Panax ginseng C.A. Meyer sold in eleven different countries had a range of total ginsenosides from 2.1% to 8.1% (for root powder) and 5.3% to 9.0% (for extract). The content and profile of commercial American ginseng products are currently unknown, but are warranted since the ginsenoside profile may possibly predict a preparation’s ability to effect glucose tolerance.
The mechanism of improved glucose tolerance with pre-administration of AG still needs to be elucidated. Based on experiments in rodents and humans, this mechanism may involve enhanced insulin secretion [37], increased insulin sensitivity [20], reduced glucose absorption [38] or a combination of these modes. As indicated in Fig. 1A, the ingestion of glucose, preceded by either placebo or 3, 6 or 9g of AG, yielded nearly identical postprandial blood glucose rises for the first 15 minutes. However, the blood glucose peaks at 30 minutes are significantly lower for all AG doses than for placebo, as are the points at 45 minutes and 60 minutes. This particular postprandial blood glucose profile resembles that seen when a meal is given with pre-administration of insulin secretagogues, including sulfonylureas, meglitinides and their related compounds [39,40]. Such oral agents attenuate rises in postprandial blood glucose by stimulating either first- or second-phase insulin release from pancreatic ß-cells [40]. Although it is speculative, there is a possibility that a component of AG also stimulates insulin release in a mode distinctive of these insulin secretagogues. Future studies, measuring postprandial insulin concentrations, should be undertaken to confirm such a hypothesized mechanism of action.
One possibility concerning the mode through which AG lowers blood glucose is that such activity is triggered only after the ingestion of exogenous glucose (as seen in this study). This concept extends from the observation that following AG consumption (i) the blood glucose concentration taken just before ingestion of the glucose challenge (time 0) remained unchanged relative to the fasting blood glucose level and (ii) the blood glucose AUC concentration after the glucose challenge decreased relative to placebo consumption.
Overall, this study represents an important step in studying herbs. In general, the supposed efficacy of medicinal herbs is underpinned by empirical or anecdotal data and tradition of use, which usually fail to meet the requirements of Good Clinical Practice [38]. Because of this, and the public’s increasing use of herbs, the medical profession has mandated that the clinical efficacy of herbs be demonstrated through randomized, placebo-controlled trials. We addressed this issue by conducting such a study, from which we concluded that the observed improvement in glucose tolerance was solely due to AG. In addition, this study was further strengthened with the dose-response design, which is also critical in drug evaluations, since it allows for the selection of the most clinically active dose [39].
The blood glucose lowering activity of AG demonstrated in normal individuals in this study may represent a novel and important preventive approach in delaying the onset of diabetes mellitus and CVD. However, before this approach is advised, further long-term studies, investigating AG efficacy and safety will have to be conducted. In terms of diabetes mellitus, the action of AG on glucose metabolism should be clinically scrutinized similarly to other alternative antidiabetic agents, namely chromium picolinate [43] and vanadium sulfate [44,45]. Long-term clinical trials with these compounds [43–45] have demonstrated improvements in glucose metabolism, and, if similar findings are shown with AG, we will possess further insight into this herb’s role in glucose metabolism and potential in diabetes mellitus.
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ACKNOWLEDGMENTS |
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Received April 12, 2000. Accepted August 28, 2000.
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REFERENCES |
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