Ginseng is a popular herbal therapy that is purported to be effective in both the prevention and treatment of diabetes. Data from studies conducted in animal models have identified ginsenoside Re as a component of ginseng that affects IS and improves glycemic control (2
). Therefore, we conducted a double-blind, randomized, placebo-controlled study to determine whether treatment with ginseng or ginsenoside Re improves oral glucose tolerance, β-cell function, and IS in humans. Only subjects with impaired glucose tolerance or newly diagnosed type 2 diabetes, who presumably have more reversible metabolic dysfunction, were studied to increase our ability to detect a beneficial effect of therapy. Moreover, we used specific sources of ginseng and ginsenoside Re that we found improved skeletal muscle IS in vitro in rodent and human muscle strips. Our data demonstrate that 4 weeks of oral ginseng and ginsenoside Re therapy do not improve oral glucose tolerance, β-cell function, or multiorgan IS. These results refute the popular notion that ingestion of ginseng and its putative active ginsenoside component has beneficial metabolic effects on glucose homeostasis.
Data from studies conducted in 3T3-L1 adipocytes and in obese, insulin-resistant rodent models have found that GRE and several ginsenoside species (Re, Rb1
) improve insulin-stimulated glucose disposal (2
). In most of these animal studies, ginseng and ginsenosides were given intraperitoneally. Oral administration of ginseng or ginsenosides has also been reported to improve oral glucose tolerance and increase insulin-stimulated glucose disposal (21
). However, the results from these studies are confounded by concomitant weight loss, so it is unclear whether the improvements in IS occurred because of weight loss or because of the insulin-sensitizing properties of ginsenosides. Few studies have evaluated the effect of ginseng in human subjects, and the interpretation of data from these studies is difficult because of differences in experimental design and contradictory results among studies. A single dose of oral ginseng given ~40 min before glucose ingestion reduced the glucose AUC during an OGTT by ~20% in some studies (23
) but had no beneficial effect in others (8
). Longer term oral ginseng therapy was evaluated in subjects with type 2 diabetes in two studies. In one study, ginseng treatment (6 g/day for 12 weeks) lowered plasma insulin concentration but did not change HbA1c
), whereas ginseng treatment (100–200 mg/day for 8 weeks) in the other study was associated with a decrease in fasting plasma glucose concentration (9
). However, the interpretation of the results from both studies is confounded by either a large drop-out rate (10
) or concomitant weight loss (9
). Oral ginseng therapy (3 g/day for 14 days) did not improve insulin-mediated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp procedure, in subjects with indinavir-induced skeletal muscle insulin resistance (24
We were unable to detect ginsenoside Re, Rb1
, or Rb2
in plasma in our subjects, even though they were prescribed large daily oral doses of ginseng and ginsenoside Re for 30 days and ingested the last dose ~30 min before a series of blood samples were obtained to assess blood concentrations. The method we used to measure ginsenoside Re, Rb1
, or Rb2
has a threshold of detection of 8 ng/mL, which is below the minimal concentration necessary for biological activity in vitro (4
). Therefore, our results suggest that ginsenoside Re is poorly absorbed from oral ingestion of ginseng or ginsenoside Re itself. The limited systemic bioavailability of ginseng Re in our subjects helps explain the discrepancy between our findings and the positive effects observed in studies that involved intraperitoneal ginseng injection (2
) or in vitro incubation with ginseng (4
). Data from pharmacokinetic studies conducted in rodents and people have found that absorption of ginseng metabolites is poor after oral ingestion (13
). Plasma ginseng or ginsenoside concentrations were not reported in previous studies that found metabolic benefits of ginseng therapy in study subjects. We are aware of only one study that evaluated oral ginsenoside absorption in human subjects (13
). This study was conducted in two subjects who were studied for 12 h after ingesting GRE. Ginsenoside Rb1
were detected at very low levels in plasma (~5 nmol/L) in one subject, but ginseng components were not detected in the other subject. Very low levels of ginsenoside Re were found in urine for up to 3 h after ingestion. The poor absorption of orally ingested ginsenosides is likely related to its saponin ring structure, which is poorly soluble in aqueous solutions. In addition, protopanaxtriols (e.g., ginsenoside Re) are rapidly hydrolyzed to ginsenoside Rb1
in mildly acidic conditions, such as in the stomach, suggesting that the bioavailability of orally administered ginsenoside Re is particularly poor. Our results, in conjunction with data from other studies, suggest that oral ginsenoside products are too poorly absorbed to provide adequate systemic availability to influence metabolic function. We cannot exclude the possibility that other ginsenosides and their metabolites or nonginsenoside components of GRE are bioavailable when given enterally.
Although it is possible that our study missed a therapeutic effect of ginseng or ginsenoside Re because of the small number of study subjects, we believe that this is unlikely. We used the hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusion, to evaluate IS. We have demonstrated that this procedure is very sensitive and reproducible (16
) and would allow us to detect a 25% improvement in insulin-stimulated glucose disposal in the current study with a power of 0.8. Our data did not even detect a trend toward treatment-induced improvement in any of our study outcome measures. Ginsenoside composition varies between commercially available products, so our study cannot eliminate the possibility that other ginseng products could have metabolic benefits.
In summary, despite the popular use of ginseng products to improve glucose homeostasis and treat type 2 diabetes, we found no evidence that oral ginseng or ginsenoside Re therapy improves β-cell function or IS in subjects with impaired glucose tolerance or newly diagnosed type 2 diabetes. Although parenteral ginseng and ginsenoside Re can markedly enhance insulin action in animal models, our data suggest that minimal bioavailability after oral ingestion limits its therapeutic efficacy in people.