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Journal of the American College of Nutrition, Vol. 20, No. 90005, 370S-380S (2001)
Published by the American College of Nutrition

Konjac-Mannan and American Ginsing: Emerging Alternative Therapies for Type 2 Diabetes Mellitus

Vladimir Vuksan, PhD,,, John L. Sievenpiper, MSc,,, Zheng Xu, MD, MSc,, Evelyn Y. Y. Wong, MSc,, Alexandra L. Jenkins, RD,, Uljana Beljan-Zdravkovic, MD, MSc,, Lawrence A. Leiter, MD,,, Robert G. Josse, MBBS,, and Mark P. Stavro, MSc,

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, CANADA
Clinical Nutrition and Risk Factor Modification Centre (V.V., J.L.S., Z.X., E.Y.Y.W., U.B.Z., A.L.J., L.A.L., R.G.J., M.P.S.), St. Michael’s Hospital, Toronto, Ontario, CANADA
Division of Metabolism and Endocrinology (V.V., L.A.L., R.G.J.), St. Michael’s Hospital, Toronto, Ontario, CANADA

Address reprint requests to: Vladimir Vuksan, Ph.D., 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


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 
Despite significant achievements in treatment modalities and preventive measures, the prevalence of diabetes has risen exponentially in the last decade. Because of these limitations there is a continued need for new and more effective therapies. An increasing number of people are using dietary and herbal supplements, even though there is a general lack of evidence for their safety and efficacy. Consequently, science based medical and government regulators are calling for more randomized clinical studies to provide evidence of efficacy and safety. Our research group has selected two such promising and functionally complementary therapies for further investigation as potentially emerging alternative therapies for type 2 diabetes: Konjac-mannan (KJM) and American ginseng (AG). We have generated a mounting body of evidence to support the claim that rheologically-selected, highly-viscous KJM, and AG with a specific composition may be useful in improving diabetes control, reducing associated risk factors such as hyperlipidemia and hypertension, and ameliorating insulin resistance. KJM has a demonstrated ability to modulate the rate of absorption of nutrients from the small bowel, whereas AG has post-absorptive effects. Consequently, it appears that KJM and AG are acting through different, yet complementary, mechanisms: KJM by increasing insulin sensitivity and AG likely by enhancing insulin secretion. Before the therapeutic potential of KJM and AG as novel prandial agents for treatment of diabetes can be fully realized, further controlled trials with larger sample sizes and of longer duration are required. A determination of the active ingredients in AG, and the rheology-biology relationship of KJM are also warranted.

Key words: type 2 diabetes mellitus, konjac-mannan, American ginseng

Key teaching points:

• With an epidemic of obesity and prolonged life expectancy, an increasing number of people are predicted to develop diabetes and die prematurely due to coronary heart disease (CHD).

• Despite substantial efforts in developing conventional medical therapies, the prevention and treatment of diabetes remain unsatisfactory, thus requiring the development of new treatment modalities.

• Substantial evidence is available to support the hypothesis that dietary fiber and herbs may be useful in the alleviation of diabetes, but the evidence is far from conclusive.

• Highly viscous dietary fiber, such as konjac-mannan (KJM) selected by rheological procedures, may ameliorate glycemic control and associated CHD risk factors in type 2 diabetes.

• Emerging evidence for the use of American ginseng (AG) in the control of diabetes and high blood pressure appears to be encouraging.

• Alternative therapies such as KJM and AG might be particularly effective in controlling the metabolic and physiologic manifestations of diabetes. They are acting through different, but complementary, mechanisms; KJM by increasing insulin sensitivity and AG likely by enhancing insulin secretion. Both insulin resistance and limited insulin secretion are important in the pathophysiology of diabetes.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 
Diabetes is a major health problem in North America reaching epidemic proportions. In the past decade, the United States has seen a dramatic 33% rise in diabetes coupled to increases in obesity and inappropriate lifestyle [1,2]. This increase in diabetes has occurred in spite of major inroads in understanding the pathophysiology and treatment of this insidious disease. Current therapies seem to be insufficient to prevent diabetic complications in type 2 diabetes, with a two- to fourfold likelihood for developing cardiovascular events [3]. Because of these limitations, there is a continuous need for the development of novel health promotion strategies and therapeutic modalities.


   Conventional Diabetes Therapies
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
Controversies
 Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 
Type 2 diabetes is a dual chronic disorder that, in the majority of patients, arises from defects in both peripheral insulin action (insulin resistance) and insulin secretion (ß-cell dysfunction), resulting in fasting and postprandial hyperglycemia [4]. The disease often co-exists with hypertension and dyslipidemia in the same individual, with devastating consequences to the cardiovascular system. Amelioration of any of these risk variables will markedly decrease the risk of cardiovascular disease (CVD) [5]. To achieve this goal, current treatment involves numerous therapies [6]: 3–4 medications for the regulation of blood glucose [7,8], 1–2 for lipids [9], and 4 to control blood pressure [10]. When hormone replacement therapy, smoking patches and aspirin [11] are added to the above, the number of required therapies increases even further. Despite this large armamentarium, the progressive deterioration of diabetes control is such that treatment is still insufficient, with the majority of type 2 diabetes patients eventually requiring insulin therapy to achieve targeted glycemic levels [12], and an estimated 75% dying of diabetes related complications from CVD [13].


   Controversies
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 
The value of current therapies is unequivocal, yet inadequate. While physicians advocate aggressive use of drugs to tighten glucose control and attenuate CVD risk factors, many patients are more inclined toward use of alternative therapies that include diet, food supplements and herbal medicine. When considering new recommendations for the treatment of diabetes [14], major health agencies and governmental authorities have largely ignored the role of diet, especially dietary fiber, and/or herbs with hypoglycemic characteristics, due to the paucity of data available. However, use of "popular" diets, nutritional supplements and botanicals is increasing among consumers. Only a minority of patients has begun to approach their physician about these types of therapies, with over 60% of patients failing to report usage of these products to their physician [15].


   Alternative Diabetes Therapies
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 
Insufficiency of current therapies for the treatment of diabetes, combined with both a lack of trust in conventional medical treatment and an inability of the economy to absorb the cost of pharmaceuticals, have created a growing public interest in dietary supplements and botanicals. The use of herbs has more than tripled over the last 10 years [15], and a whole new industry referred to as "nutraceuticals" has evolved. Similarly, consumption of dietary fibers such as wheat bran, psyllium and oats has increased significantly, due mainly to the conduct of research promoting their health properties and providing evidence to permit the approval of health claims by the FDA [16]. While therapeutic potential of dietary fibers in reducing serum cholesterol and maintenance of colonic health has been well recognized, their hypoglycemic effects are much less well established. In the case of herbs, the safety and efficacy of alternative therapies for the treatment of diabetes remain largely unknown. A vast abundance of knowledge is present and is based on open case studies, animal studies and in vitro experiments, false claims, paraherbalism and soft science. The medical literature and popular press are replete with anecdotal evidence both with respect to the efficacy and detrimental effects of herbs and novel fibers for the treatment of diabetes. The medical community and governmental agencies have responded with a call for more controlled clinical assessments of the efficacy and safety of nutritional supplements and botanicals [17].


   Research Objectives
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
 Research Objectives
KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 
With a clear clinical need to investigate novel strategies, we endeavored to probe the efficacy and safety of two therapies as possible adjuncts and/or alternatives to conventional treatment for diabetes mellitus. The first therapy involves the use of a novel fiber extracted from the root of the Konjac plant (Amorphophallus Konjac, K. Koch). This is a highly viscous fiber that targets gut absorption phenomena and possibly increases insulin economy [18,19]. The second alternative therapy under development is American ginseng (AG) (Panax quinquefolius L.), a popular herbal medicine that may target post-absorptive physiological mechanisms and might have insulin secretagogue properties. These treatment modalities were selected by our laboratory for further investigation based upon our years of experience studying the relationship between the rheological properties and physiological effects of soluble fiber, and more recent work into the physiological effects of adaptogenic and hypoglycemic herbs.


   KONJAC-MANNAN (KJM)
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 
Background
For a thousand years in Asia, the tuber root of the konjac plant has been used as a foodstuff and remedy. KJM flour is obtained from grinding the konjac plant root and is traditionally made into a rubbery gel and eaten. Only recently has purified KJM flour been used as a stabilizer or gelling agent in variety of food applications, and as a food supplement in the production of health food products [20]. It has generally recognized as safe status (GRAS) in the U.S., and "novel" food status in Canada. Its main constituent is highly viscous glucomannan, a polysaccharide chain containing glucose and mannose in a molar ratio of 1:1.6 with ß-1-4 linkages. When taken as a supplement, it has been shown to reduce serum lipids and systolic blood pressure [21], postprandial glycemia [22], and body weight [23].

Rheological Studies
Viscous fibers, as a result of their rheological (flow) properties, reduce postprandial increases in plasma glucose and insulin concentrations in normal and diabetic subjects [24–27]. There is now convincing evidence that the effectiveness of gel-forming fibers seems to relate mainly to their capacity to hydrate rapidly and thus increase the viscosity of digesta in the stomach and small intestine. These properties are dependent on fiber concentration, molecular weight, and also size-distribution of the fiber-gum particles [28].

KJM is very important in this regard for, when properly selected, it may have the highest viscosity amongst polysaccharides. We determined the viscosity of KJM (92% glucomannan), psyllium (95% purity), and xanthan using a Brookfield viscometer. When measured at 1% concentration, shear rates of 6, 12 and 30 sec-1, using spindle setting F and 22 degrees centigrade, the apparent viscosity for KJM was 12 x 10-1 cp, which was twofold higher than xanthan 6.2 x 10-1 cp, and almost six times that of the psyllium 2.1 x 10-1 cp [26]. The flattening of postprandial glycemia, following 20 grams of glucose challenge and 3 grams of fiber added, closely mirrored the relative viscosity of the fibers, with KJM demonstrating the greatest effect followed by xanthan and psyllium (Fig. 1) [26]. In the selection of KJM material for our clinical studies we used glucomannan that had both a high level and a homogeneous distribution of molecular weight, in addition to a high presence of branching. The target molecular weight of KJM fiber typically used in our clinical experiment exceeds 100 x 10-4, determined by light scattering measurements.



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  		Fig. 1. Postprandial glycemic responses to a 20 g oral glucose challenge done alone ({circ}) or following 3 g of psyllium ({lozenge}), xanthan ({square}), or konjac mannan ({blacktriangleup}) (A) and the calculated glycemic indexes of three fibers relative to oral glucose alone (B). GI was expressed as the area under the curve (AUC) for each fiber divided by the AUC for oral glucose alone multiplied by 100. Points or bars with different letters are significantly different (repeated measures ANOVA adjusted for multiple pairwise comparisons with the Newman Keuls procedure, p < 0.05). Statistics expressed for GI differences were done for the differences in the absolute AUC values. Data are mean ± SEM. Reference [26].

 
Furthermore, we exploited the ability of KJM to act synergistically with other polysaccharides, forming a gel with unique viscoelastic properties [20,26]. An interaction of the cellulosic backbone of other polysaccharides and the mannan backbone of KJM results in a considerable increase in viscosity of the mixed KJM polymer, and thus significant improvements in lipid and carbohydrate metabolism in humans (Proprietary Technology: Provisional U.S. Patent #60/208,090). We studied the effect on glycemic response of incorporating our high viscosity proprietary KJM-polysaccharide mix in a group of seven type 2 diabetic individuals with mean ± SD age = 54 ± 7, BMI = 27 ± 3, and HbA1C = 7.6 ± 1.2%. Three grams of proprietary KJM mix were added to a 50 gram available carbohydrate portion of test biscuit and compared to matched control biscuits consumed on two different occasions. Blood glucose was measured over two hours following consumption of the test meals, with postprandial glycemia calculated as the incremental area under the glucose response curve expressed as a percent of mean of control biscuits. The glycemic index was 42 ± 5 [27]. This exceptional reduction, achieved with a relatively low, almost pharmacological concentration of KJM mix, indicates that KJM offers great potential for use in a variety of functional foods for the management/treatment of diabetes.

From acute glucose challenge studies we moved to test the potential effect of this fiber as part of a well-controlled long-term study. The KJM polymer, which had been proven to be the most potent, was incorporated into the palatable test biscuits and matched with control biscuits that were substituted into a National Cholesterol Education Program (NCEP) step 2 diet in two long-term studies. Both types of biscuits were provided by Dicofarm S.p.a., Rome, Italy. The two studies conducted were both randomized, placebo-controlled, metabolic feeding (food delivered to the study participants) trials, with crossover phases during which participants maintained their habitual body weight and medications.

Study 1: KJM and Type 2 Diabetes
The first study was conducted in high-risk subjects with type 2 diabetes receiving concurrent pharmacological treatment for diabetes, hypertension, and dyslipidemia [29]. The KJM treatment was well tolerated with only transient effects on the colon as observed from increased flatulence and rare cases of mild diarrhea. The main findings included significant improvements in glycemic control, serum lipids and systolic blood pressure compared to placebo biscuits (Fig. 2). Because these improvements were seen beyond the NCEP Step 2 diet and medications alone, it was suggested that KJM might augment conventional dietary and pharmacological treatment safely in people with type 2 diabetes with associated CVD risk factors.



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  		Fig. 2. Percent change in (A) measures of glycemic control (fasting plasma glucose, plasma insulin, and serum fructosamine) and systolic blood pressure and (B) measures of serum cholesterol (total, LDL, total:HDL ratio, and apolipoprotein B-100 [Apo-B]) after 3-weeks of supplementation with either konjac mannan (KJM, {blacksquare}) or wheat bran (WB) control ({square}) biscuits in 11 subjects with type 2 diabetes mellitus, hyperlipidemia, and hypertension receiving a metabolically controlled National Cholesterol Education Program (NCEP) step 2 diet. p-values are for a GLM ANCOVA, adjusted for repeated measures, starting value, randomization sequence, diet, age, and gender. Data are mean ± SEM. Reference [29].

 
Study 2: KJM and Insulin Resistance Syndrome
Similar results were found in the second study in subjects selected for the full cluster of features of the insulin resistance syndrome: impaired glucose tolerance, dyslipidemia (low HDL, elevated triglycerides), central obesity, mild hypertension, and increased apolipoprotein (apo) B [30]. Reductions were observed in glycemia, blood lipids, and lipid ratio, and improvements were found in apolipoproteins compared with placebo (Fig. 3).



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  		Fig. 3. Percent change in (A) measures of glycemic control (fasting plasma glucose, plasma insulin, and serum fructosamine) and systolic blood pressure and (B) measures of serum cholesterol (total, LDL, total:HDL ratio, and apolipoprotein B-100 [Apo-B]) after 3-weeks of supplementation with either konjac mannan (KJM, {blacksquare}) or wheat bran (WB) control ({square}) biscuits in 11 subjects with the insulin resistance syndrome (IGT, dyslipidemia, central obesity, mild hypertension) receiving a metabolically controlled National Cholesterol Education Program (NCEP) step 2 diet. p-values are for GLM ANCOVA, adjusted for repeated measures, starting value, randomization sequence, diet, age, and gender. Data are mean ± SEM. Reference [30].

 
An improvement was also observed in whole body insulin sensitivity as calculated by equation of Matsuda et al. [31]. These measurements were calculated and compared using postprandial glucose and insulin profiles taken after KJM or control mixed meal challenges consumed at the beginning and end of each 3 week study period [32]. It was concluded that, beyond a NCEP step 2 diet alone, KJM supplementation improved features of the insulin resistance syndrome including insulin action and LDL-apo B.

KJM Versus Other Therapies
These effects of KJM compare well against other therapies. Although KJM improved glycemic control only mildly, the reductions were comparable to those found with oral hypoglycemic agents such as alpha-glucosidase inhibitors (i.e. Acarbose) [33]. KJM also demonstrated very strong lipid lowering effects. It had an effect greater than that of other refined but "non-rheologically selected" KJM varieties [21,33,34]. Lipid lowering effects of KJM seen in our two studies were comparable to those of low dose statin drugs. Compared to lipid lowering effects of major gel-forming fibers such as psyllium, oat, or guar [35], KJM has three- to fivefold stronger effects (Fig. 4), expressed as a change in cholesterol per gram of soluble fiber consumed.



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  		Fig. 4. Comparison of the total and LDL cholesterol lowering ability of the 4 main dietary soluble fibers (psyllium, oats, guar gum, and pectin) versus KJM. Values for the 4 fibers are taken from the meta-analysis of Brown et al. [35] and values for KJM represent the mean reduction in cholesterol taken from the two studies by Vuksan et al. [29,30]. Data are presented as change in cholesterol (mmol/L) per gram of soluble fiber.

 
Proposed Mechanisms
The mechanism by which KJM improves metabolic control likely involves its rheological properties. It has been repeatedly shown that measures of viscosity and hardness of KJM and other soluble fibers are inversely correlated with postprandial glycemia [16,24–26]. It is hypothesized that the gel forming KJM, like other soluble fibers, increases the viscosity of the digesta slowing the rate of food absorption in the small intestine, thereby decreasing postprandial glucose and insulin surges. This in turn may result in a long-term improvement in peripheral insulin sensitivity. These effects may also explain KJM’s cholesterol lowering properties. KJM also has been shown to inhibit cholesterol absorption in the jejunum [36] and bile acid absorption in the ileum [37], contributing to improvements in plasma LDL and apoB levels. However, these effects may also be mediated by decreased shunting of glucose and fatty acids through the liver and decreased VLDL synthesis. Thus a series of major vascular and CVD risk factors are improved such as dysglycemia, dyslipidemia, and hypertension in people with type 2 diabetes, and glucose, lipid control and insulin resistance in people with the insulin resistance syndrome. If KJM is operating through this mechanism, then its higher viscosity compared to other soluble fibers may explain its higher lipid lowering capacity. Another physiological response, which may be a response to consumption of KJM fiber, might be blood pressure. The attenuated increased insulin sensitivity [38] might reduce blood pressure by influencing sodium absorption in the distal tubule, increasing sympathetic nervous system activity and decreasing peripheral vascular resistance [39]. Such an improvement in insulin sensitivity might have been mediated by sustained slowed absorption during the KJM treatment.


   AMERICAN GINSENG (AG)
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
IMPLICATIONS
 REFERENCES
 
Background
For the last 3000 years of Chinese traditional medicine, the root of ginseng species has been used as a tonic with supposed curative, restorative and aphrodisiac properties. Trust in health properties of ginseng is best supported by consumption, which exceeds $300 million in the USA alone [15]. However, most of the claims made for ginseng are anecdotal, or based on cellular and molecular research, as well as animal studies, with lack of demonstrated effect in humans for any of the claimed therapeutic properties [40]. There are fourteen species of ginseng, including AG (Panax quinquefolius L.), Asian (Panax ginseng C.A. Meyer), Japanese (Panax Japonicus CA Meyer), san-chi (Panax Notoginseng [Burk.] F.H. Chen), and the non-panax species Siberian (Eleutherococcus Senticosus). Only recently have tests of their effects using rigorous scientific techniques begun in humans. From the little that has been learned from these tests, the WHO continues to endorse ginseng as an herb without known side-effects [41]. Other investigators, however, have cited side effects that include increased blood pressure, nausea, headache, insomnia, nervousness, and diarrhea [42]. Interaction with "blood thinning" agents is another non-confirmed possibility [43]. According to the American Herbal Products Association’s Botanical Safety Handbook, most of these adverse effects can be attributed to Asian ginseng, with no reported adverse effects for AG [44].

Growing evidence from in vitro and animal models indicates that ginseng might have a viable use in diabetes. North American [44–46], Chinese [46,47], Siberian, Sanchi, and Korean Red (steam treated Panax ginseng C.A. Meyer) [47] ginsengs have been shown to possess significant hypoglycemic action in rodent models. The same is true for some of their fractions: saponins (ginsensoides), peptidoglycans (panaxans for the panax species and eleutherans for Eleutherococcus senticosus), and the water (DPG-3-2) and methanol (EPG-3-2) extracted fractions of Chinese ginseng [48]. The sole human long-term study that investigated ginseng in diabetes also offers support. Supplementation for eight weeks with 200 mg/day of an unspecified type of ginseng extract resulted in an improvement in long-term glycemic control measured by hemoglobin A1c [49]. This observation however was complicated by significant weight reduction.

Acute Studies
Using traditional Chinese medical teachings to establish starting points for ginseng dosing and timing applications, we evaluated the efficacy of AG on postprandial metabolism in a series of four acute studies (Table 1). AG was administered at doses from 1 to 9 grams and at times of administration from 0 to 120 minutes before an oral glucose challenge in people with and without type 2 diabetes [50–53]. Taken together, AG demonstrated a good acute safety profile. Neither group of subjects reported side effects, with the exception of insomnia reported by a diabetic patient after AG in our first study [50]. The data also suggested that escalation of dose and time of administration offered no added benefit in people with diabetes. Doses of 3, 6, and 9 grams and administration times of 120, 80, 40, and 0 minutes before a 25 gram oral glucose challenge were equally as efficacious at lowering postprandial blood glucose from 15–20% compared to placebo [51]. These reductions were achieved without an effect on glycemia before the oral glucose challenge. Effects were also observed beyond the oral hypoglycemic medications in which 6 of 9 subjects remained constant in the first acute study and 7 of the 10 remained constant in the second study. Taken together, the data suggested the possibility for an adjunctive role of AG in lowering postprandial glycemia without the fear of precipitated preprandial hypoglycemia. This last safety feature may confer a benefit of AG over the sulfonylurea drugs and hormones, which currently are common treatment in type 2 diabetes.


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  		Table 1. Summary of Four Acute American Ginseng (AG) Studies in People with and without Type 2 Diabetes Mellitus

 
Similar findings were observed in people without diabetes, with one exception. Again there appeared to be no dose response. In one study, doses of 1, 2, and 3 grams of AG were equally efficacious at lowering postprandial glycemia compared to placebo [52], while in another study the same was true for doses of 3, 6, and 9 grams [53]. People without diabetes however appeared sensitive to the time of ginseng administration. Reductions were achieved when times of administration were 40, 80, and 120 minutes before the oral glucose challenge [54], but not closer to the challenge. Times of administration of 20, 10, or 0 minutes before the challenge did not result in postprandial blood glucose reductions [52]. Again, reductions were achieved without an effect on glycemia before the oral glucose challenge in all cases. It was concluded that the dose response for AG probably lies below 1 gram and that AG’s blood glucose lowering effect appears time dependent in people without diabetes.

The AG used in all four acute studies originated from the same batch. The composition of this specific AG was characterized by a higher portion of protopanaxadiols relative to protopanaxatriols, with ratios of Rg1/Re and Rb2/Rc smaller than 1. Because it is difficult to establish that the ginsenoside profile of ginseng is responsible for its effects in the absence of similar studies using ginseng with varying ginsenoside composition, we were reluctant to draw such a conclusion.

Long-term Study
Armed with our dosing and timing response data, we conducted a long-term study in people with type 2 diabetes [54]. We hypothesized that the postprandial blood glucose lowering effects we observed following 1 gram of AG could be sustained safely in type 2 diabetic subjects. This hypothesis was tested using a double blind, placebo-controlled crossover trial. Twenty-four well-controlled (HbA1C = 7.1 ± 0.1%) type 2 diabetic subjects (F = 11; M = 13; Age = 64 ± 7; BMI = 28 ± 5 kg/m2) were randomized to consume 1 gram of a standardized AG extract (CNT2000 produced by Chai-Na-Tai Corporation from Langley, BC, Canada) or placebo before each meal three times daily for eight weeks while following a Canadian Diabetes Association diet. Seventeen of the 24 subjects who were having their diabetes treated pharmacologically were also maintained constant on their medications throughout. After the first treatment phase, all subjects were washed out for at least 4 weeks and then crossed over to receive the alternate treatment. Plasma HbA1c, glucose, and insulin were measured as primary endpoints. Because numerous articles, commentaries, and editorials have cautioned that ginseng may increase blood pressure, this safety parameter and others were measured as secondary endpoints. Preliminary results from the study [54] demonstrated that consumption of AG extract modestly but significantly reduced HbA1c compared with placebo. As well, fasting blood glucose significantly decreased (0.95 mmol/L; p < 0.027) with eight weeks of AG treatment, while insulin increased nonsignificantly compared to placebo. The unexpected finding was a significant decrease in blood pressure on AG, with an end difference between AG and placebo for systolic blood pressure of 5.6 ± 2.7 mmHg (p = 0.001, adjusted for age, gender and starting value). It is important to mention that 15 subjects were taking hypotensive medications. Liver and kidney functions were not affected by either treatment. We concluded that an AG extract added to the conventional treatment of diabetes significantly improved glycemic and blood pressure control beyond conventional treatment alone.

Proposed Mechanisms
Although the mechanisms underlying AG’s hypoglycemic action are still elusive, animal data support several possibilities that may work alone or together. These include three possibilities: (1) modulation of glucose disposal [55–57], 2) insulin secretion [58,59], and (3) digestion [60]. The last of these possibilities seems unlikely. Whereas KJM might have modulated digestion through a gut effect, our blood glucose data from the acute studies would seem to suggest that AG does not. The reductions in glycemia were observed consistently in the final 60–90 minutes of the oral glucose challenges. If AG were able to slow digestion, then, as seen with soluble dietary fiber and Acarbose, we also would have expected lower values in the first 15–30 minutes, the absorptive phase of the blood glucose profile. Preliminary mechanistic trials that include acute insulin data on eight male and female nondiabetic subjects (age: 34 ± 3; BMI: 24.6 ± 0.8 kg/m2) offer stronger support for post-absorptive effects, such as an enhancement of insulin secretion [61]. We observed that 6 grams of AG administered 40 minutes before a 75 gram oral glucose test (75g-OGTT) increased postprandial insulin concentrations ~2-fold in the first 45 minutes following the challenge compared to the 75g-OGTT done alone previously (Fig. 5). As the first 60 minutes of a 75 gram oral glucose challenge is considered to be representative of the early phase of insulin secretion, these data suggest that AG may be able to increase this phase, the loss of which is a primary defect in type 2 diabetes. Also offering support to an insulin enhancing effect of AG is the nearly significant (p = 0.084) ~25% increase that was observed in fasting insulin after eight weeks of AG supplementation in the long-term study.



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  		Fig. 5. Incremental change and area under the curve (AUC) in plasma (A) glucose and (B) insulin following America ginseng (AG) taken 40 minutes before ({blacktriangleup}) or together ({triangleup}) with a 75 g oral glucose tolerance test (75 g-OGTT), or a 75 g-OGTT done alone ({circ}) in 8 nondiabetic subjects. Points or bars with different letters are significantly different (repeated measures ANOVA adjusted for multiple pairwise comparisons with the Newman Keuls procedure, p < 0.05). Data are mean ± SEM. Reference [61].

 
Involvement of ginsenosides may play an important mechanistic role [56–60]. The 20 (S)-protopanaxadiol ginsenoside Rb1, measured in our studies, was found to increase glucose uptake into sheep erythrocytes in a dose dependent manner. Another protopanaxadiol we measured, Rb2, was also shown to increase the activity of the rate limiting glycolytic enzymes, glucokinase and phosphofructokinase, while decreasing the activity of the rate limiting gluconeogenic enzyme glucose-6-phophatase in rat liver preparations [56–58]. Taken together, it is tempting to suggest that these ginsenosides present in our AG might be responsible for the observed reductions in postprandial glycemia and improvements in glycemic control over the eight weeks of our study. However, evidence is insufficient to make this extrapolation. Neither studies that investigated the effect of isolated ginsenosides on carbohydrate metabolism in humans, nor direct investigations of the hypoglycemic activities of the more than 20 other ginsenosides can be found in the literature.

CONCLUSIONS
Our preliminary data indicate that both KJM and AG may have therapeutic promise in the treatment of diabetes. These two alternative therapies provided benefits to a number of physiological risk variables that worked independently of the diet and in addition to concurrent medications. Overall, KJM and AG both target meal related metabolic excursions safely, with mechanisms that appear to be different but complementary to each other; KJM by decreasing nutrient absorption rates and increasing insulin sensitivity and AG by enhancing insulin secretion.


   IMPLICATIONS
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
REFERENCES
 
Although our data suggest that the concurrent use of KJM or AG with other oral agents to treat diabetes, hypertension, and dyslipidemia might improve treatment outcomes safely, an interaction with other therapies remains an unconfirmed possibility. Since both KJM and AG exert their effects beyond conventional treatment, there is a suggestion that adverse outcomes may be precipitated. These might include undesired postprandial hypoglycemia, although this has not been observed in any of our controlled studies. Whether these therapies are helpful in the long run is not known. Practitioners should therefore make themselves aware of any alternative treatments used by their patients since the patients may choose to use KJM and AG as a preemptive measure to drug therapy or adjunct to conventional drug treatment. However, before physicians can prescribe these as "mainstream alternative therapies" much more research is needed. The mechanisms for each and their long-term effects are areas requiring more study. Other avenues of investigation include exploring ways to enhance the metabolic effects of KJM through modulation of its rheological characteristics, development of new products, and initiation of longer-term studies. Confirming the unexpected blood pressure lowering effect of AG and the mechanisms involved is of extreme interest and gives credence to the overall health benefits of ginseng, which is sometimes referred to as an adaptogen or "normalizer" of multiple physiological functions [62]. Another study of great potential is a "head-to-head" comparison of various ginsengs to determine whether the effects observed with AG hold for other varieties and species, while shedding light on potentially interesting chemical composition differences as they relate to physiological effects. Finally, the isolation and optimization of active components from AG specific to various physiologic variables will provide much interesting work for years to come.


   FOOTNOTES
 
Dr. Vuksan has received research and travel grant from Ministry of Agriculture, Food and Rural Affairs, Agriculture and Agri-Food Canada (Ontario Tobacco Diversification Program) Ottawa, Ontario; Chai-Na-Ta Corp., Langlay British Columbia, Canada; and Dicofarm S.p.a. Rome, Italy.

Received April 26, 2001.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Conventional Diabetes Therapies
 Controversies
 Alternative Diabetes Therapies
 Research Objectives
 KONJAC-MANNAN (KJM)
 AMERICAN GINSENG (AG)
 IMPLICATIONS
 REFERENCES
 

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