The incidence of type 2 diabetes mellitus (T2DM) has been rising at an alarming rate over the last 2 decades and it is now considered to be a global epidemic. Latest statistics indicate that it affects 382 million people worldwide, with projections of a 55% increase by 2035 [1]. T2DM compounds an individual's risk for developing cardiovascular disease (CVD) [2]. Prolonged hyperglycemia and vascular abnormalities, the physiological hallmarks of diabetes, result in diabetes related micro- and macro-vascular complications [3]. As such, tight glycemic control and well managed blood pressure (BP) are fundamental to achieving optimal diabetes care [4]. However, these treatment goals generally go unmet [5], as recent estimates revealed that only half of the diagnosed individuals with diabetes are meeting their glycemic targets, and only 36% are achieving goals for blood pressure [6]. The progressive nature of the disease, along with the unmet treatment challenges generates a compelling argument for safe, effective, and affordable alternative treatments that can be used as an adjunct to current medical therapies. Concurrent with the increasing demand for more effective medications is the recent upsurge in the use of herbal remedies amongst the general public [7].

Ginseng, a traditional medicinal plant, embodies an important position in the oriental pharmacopeia. Traditionally, it is used primarily for treating illness, restoring homeostasis, and promoting longevity [8], but more recently it has been identified as the most commonly used herb for controlling CVD factors [8]. Of the thirteen ginseng species identified, the most commonly consumed and well established therapeutic herb is Asian ginseng (Panax ginseng) [9]. More specifically, varieties of Korean red ginseng (KRG), a type of Asian ginseng, have been shown to improve glycemic control and certain cardiovascular parameters when used in addition to conventional medication [10,11,12]. However, despite it being the most popular form of ginseng used in traditional dishes [13], scant clinical evidence exists on the health benefits of the white, non-steamed cultivars of Korean ginseng, Korean white ginseng (KWG). It has been suggested that steaming results in a more pronounced biological effect compared to raw dried ginseng [14], however the the process significantly alters the profile of dammarane type saponins, a pharamacologically active fraction of ginseng, also known as ginsenosides [15], and also results in loss of malonyl type ginsenosides [16,17], all of which may possibly alter its therapeutic benefits. Given the favorable metabolic properties of KWG seen in animal models [18,19] along with the added cost of steaming of KRG [20], KWG may hold promising potential in improving certain CVD risks, and thus, serve as a less expensive therapeutic alternative to KRG. As clinical data on its medicinal properties is relatively scarce, there is a compelling need for exploring its CVD health benefits. Therefore, the objective of this exploratory study was to investigate a dose-response relationship between escalating doses of KWG and its effects on vascular and glycemic parameters, which may lead into potential long term benefit exploration.

We present here, for the first time, that KWG - the most commonly consumed form of ginseng in Korea [13] - exhibits a favorable acute effect on AI, a marker of arterial stiffness, in individuals with T2DM. More specifically, we show that this effect is associated with the consumption of 3 g KWG dose, and the effect appeared to not be dose dependent. These findings are of interest given the well-established predictive ability of AI in determining future CVD events [21,22]. Our results also indicate that KWG does not significantly reduce postprandial glycemia relative to control. A U-shaped relationship was observed between escalating doses of KWG and PPBG, with 3 g KWG showing the greatest reduction, and 6 g KWG eliciting an increase, albeit not significant.

Arterial stiffness has emerged as a novel marker of CVD risk, displaying a clear independent predictive value [22,23]. As such, acute improvements in AI demonstrated with 3 g KWG may have a clinical potential, and could aid in broadening our understanding on the hemodynamic potential of ginseng.

The acute effects seen on AI add to those from previous clinical trials though different ginseng species and varieties were explored. In an acute randomized controlled trial, 3 g KRG significantly lowered arterial stiffness in healthy individuals, relative to control, with no improvements in BP [11]. Another recent study conducted by our group in individuals with T2DM and concomitant hypertension showed that 3 g American ginseng (AG) significantly lowered radial AI and attenuated systolic BP after 12 weeks of consumption [24]. Conversely, our results are not in line with data from two studies where 3 g and 4.5 g of KRG administered daily for 3 months did not improve arterial stiffness in subjects with metabolic syndrome and hypertension [25,26]. The inconsistency in the findings could be possibly attributed to the differences in the method by which arterial stiffness was assessed in the current (radial pulse wave analysis) versus the two studies (brachialankle pulse wave velocity).

Accumulating data from animal and in vitro work have demonstrated that certain ginsenosides, such as Rb1, Re, and Rg1, display cardioprotective effects, chiefly on vascular endothelial function via endothelium dependent release of nitric-oxide (NO) [27,28,29]. In view of the clinical implications linking arterial stiffness and endothelial dysfunction to decreased NO generation and increased NO inactivation [30,31], together with evidence from preclinical data, the beneficial AI findings seen with 3 g KWG may be possibly explained by NO driven mechanism stimulated by these ginsenosides, including Rb1, Re, or Rg1, two of which (Re and Rg1) were found to be present in fairly similar concentrations as in our efficacious KRG roots [11]. While it is tempting to attribute our favorable vascular observation to these ginsenosides, the possibility that other potential active fractions of ginseng, including unmeasured ginsenosides, polysaccharides, peptides, fatty acids, and polyacetylenic alcohols might have played a role, cannot be eliminated [8].

The lack of a significant amelioration in peripheral systolic BP is not unexpected and is partly in line with our previous observations, where KRG showed either neutral or moderate effects [11,32]. Although KWG did not lower BP relative to control, the neutral BP observations are significant in light of the concern in the literature that ginseng may increase blood pressure [33], which resulted in advice given to individuals with hypertension to avoid ginseng products. Thus, this study adds further information on the safety of ginseng in hypertension.

An extensive number of clinical, laboratory and animal studies have investigated the therapeutic potential of ginseng in improving glycemia, with much focus being placed on two species: Asian, typically the steamed variety of Korean ginseng, and AG [34,35]. Presently, a number of reports from animal models reveal a possible anti-diabetic potential of the non-steamed variety of Asian ginseng [18,36,37,38]. Yet, to date, no randomized controlled trials have explored the acute glycemic and vascular effects of such varieties in T2DM. With respect to findings seen with other ginseng species and types, our results do not demonstrate a favorable acute glycemic effect as observed with the original efficacious batch of AG following standard oral glucose tolerance test (OGTT) in both healthy and subjects with T2DM [39]. As well, our findings are inconsistent with the favorable postprandial glycemic results of Panax ginseng extracts (Ginsana G115) and KRG rootlets, seen either alone or with standard glucose tolerance tests in healthy individuals [40,41]. On the other hand, we are only aware of two studies that have assessed the acute glycemic effects of the non-steamed Asian ginseng variety in healthy subjects. In these studies, both null and opposing glycemic effects were observed with single and combined ginseng doses following a 75 g-OGTT [42]. In relation to these two studies, we show similar null but not increasing glycemic effects following acute administration of escalating KWG doses. Comparing the total ginsenoside profile of the present ginseng to the one used in these two studies reveals that the concentration in the present sample is nearly twice as much (1.8% vs. 0.8% ginsenosides). However, despite having a greater ginsenoside concentration, as well as including subjects with T2DM, no glycemic lowering benefits were observed. On the other hand, our neutral glycemic observations are in contrast with evidence from animal studies [18,36]. In a recent 3 week investigation, it was found that the malonyl ginsenosides, a type of ginsenosides that exist in both fresh and air dried (non-steamed) root, significantly lowered fasting blood glucose when given at 50 and 100 mg/kg/wt doses to high fat diet fed and streptozotocin-induced diabetic rats [43]. As well, a previous study showed that 4-week oral administration of both white ginseng radix and rootlet lowered fasting blood glucose levels in KKAy mice compared to controls [18].

Reasons for the discrepancies in our glycemic findings are unclear. Variability in the ginsenoside profile might partially provide some explanation [44]. Analysis of ginsenoside profile revealed that the total ginsenoside content (1.8%) of the current ginseng variety was almost half of that found in our original efficacious batch of AG (3.2%) [39]. The optimal PPD:PPT ratio was found to be lower by 8-folds (0.35 vs. 2.44), and the relevant glycemic lowering ratios for Panax ginseng C.A Meyer (Rg1:Re and Rb2:Rc < 1) were not met [45]. Additionally, the concentration of individual PPD ginsenosides, including Rb1 and Rc, that have previously shown a glycemia lowering potential in animal models when provided at levels greater than 1, was not satisfied [46]. The implication is that it is possible that the main ginsenosides that have previously demonstrated hypoglycemic effects were not meeting their efficacy range. In line with this paradigm, we can speculate that the observed U-shaped dose-response relationship may be allocated to the level of available bioactive components, representing the fundamental nature of a pharmacological agent where biological activity is either below the threshold, as observed with 1 g KWG, or above the threshold with the upper dose of 6 g KWG. It is possible that substrate saturation is reached at a higher dose of KRG where no further benefit, followed by a possible counteractive effect, may be observed. Taken together, 3 g KWG appears to be the most optimal dose of KWG tested that can potentially improve glucose metabolism, which is in line with the dose range suggested within ginseng monographs based on traditional recommendations [47].

Two limitations to this work must be addressed. First, we assessed the vascular and glycemic health effects of KWG in an acute design. It is thus unclear whether continuous long term administrations would yield similar results. Secondly, the subjects were taking diabetes and antihypertensive medications. Though these medications were not taken on morning visits, they were taken 12-24 hrs prior to the visits. Hence, they or their metabolites might have been present in the blood on test mornings, and could have potentially confounded the participants' vascular and glycemic measures.

In conclusion, the current study is the first to explore the vascular and glycemic effects of KWG in subjects with T2DM. It showed that acute administration of 3 g KWG elicited modest but significant reductions in arterial stiffness, as measured by AI, while BP and glycemia were not affected. Interestingly, the optimal dose where greatest improvements were seen across vascular and glycemic parameters appears to be the 3 g dose which were not observed with either the 1 or 6 g doses. In light of such findings, future studies should aim at exploring the long term vascular and glycemic effects of the optimal dose identified herein, 3 g, with a main focus in determining its contributing constituents. Should the beneficial results on AI observed in this study be validated in longer term trials, the 4-yr old KWG root may be a promising candidate that is comparable in efficacy to the typically endorsed and valued 6-yr old KRG, creating significant economic possibilities in the area of evidence-based remedies for CVD risk reduction.