Kenneth S. Polonsky, M.D.
Project Overview:
Subjects with impaired glucose tolerance (IGT) are at particularly high risk for diabetes; over time, 50% or more will develop overt diabetes. Ginseng root is one of the most commonly used natural remedies in the United States and has been purported to improve glucose tolerance and prevent diabetes. Ginsenoside Re, a major constituent, has been implicated in the anti-diabetic effects of ginseng. The already widespread use of ginseng by the general population make it a potentially appealing agent for the prevention and/or treatment of type 2 diabetes, if safety and efficacy could be demonstrated in carefully cont rolled clinical studies. The present proposal details plans to study the metabolic effects of ginseng and ginsenoside Re in subjects with impaired glucose tolerance. The specific aims are: 1. To determine the effect of ginseng extract and ginsenoside Re on: a) glucose tolerance, b) basal glucose production, glucose disposal and lipolytic rate, and c) insulin action in adipose tissue, liver, and skeletal muscle. The hypothesis will be tested that ginseng extract and ginsenoside Re will improve glucose tolerance in subjects with IGT by decreasing basal glucose production and lipolytic rates and enhancing insulin-mediated suppression of glucose Ra and glycerol Ra, and stimulation of glucose Rd. 2. To determine the effect of ginseng extract and ginsenoside Re on pancreatic beta-cell function. The hypothesis will be tested that ginseng extract and ginsenoside Re will improve pancreatic beta cell sensitivity to glucose in subjects with IGT. 3. To determine the effect of ginseng extract and ginsenoside RE on skeletal muscle insulin signaling. The results from this study could lead to the development of a new and important approach to the prevention and/or treatment of type 2 diabetes, if the hypotheses posed above prove to be correct and if ginseng and/or ginsenoside Re are well tolerated.
Progress Report:
We have evaluated insulin action in 15 obese subjects with impaired glucose tolerance before, and 4 weeks after random assignment to either placebo, ginsenoside RE, or ginseng. Subjects underwent frequent visits during treatment to monitor for side-effects of treatment and to ensure weight stability during the study period. Groups were matched with respect to age, body mass index (BMI) and body composition (i.e., % fat mass).
Body weight, body composition, HbA1C, fasting plasma lipids and glucose concentration were not different between groups before treatment, and did not change during 4 weeks of treatment in any of the groups. Fasting plasma insulin concentration was similar between groups during fasting conditions and did not change during 4 weeks of treatment in any of the experimental groups. Insulin infusion during the euglycemic hyperinsulinemic clamp resulted in an increase in plasma insulin concentration and was not different between groups before (77 ± 5 µU/ml, 85 ± 7 µU/ml, 78 ± 12 µU/ml, P=NS) or during treatment (74 ± 6, 87 ± 5, 76 ± 10 µU/ml, P=NS) in control, ginsenoside RE and ginseng-treated groups, respectively. Prior to therapy, fasting whole-body lipolytic rate (glycerol release into plasma (Ra)) was not different between groups and did not change during 4 weeks of treatment (Table 2). The ability of insulin to suppress glycerol Ra was not different between groups before or following drug therapy. Before treatment, endogenous glucose release into plasma (glucose Ra) was similar between groups during fasting conditions and was suppressed to a similar degree by insulin infusion in all groups. Glucose Ra during basal conditions and during insulin infusion was not different after four weeks of drug therapy in any of the experimental groups. Insulin infusion increased glucose disposal (Rd) in all groups and was not different between groups during insulin infusion. Glucose Rd during insulin infusion did not change in any of the experimental groups following drug therapy.
Initial testing by the supplier revealed metabolically active compounds of Ginseng/ginsenoside RE as demonstrated by in vitro testing in laboratory rats. However, once the data from the human subjects was analyzed and no significant metabolic effects were noted, testing was performed by Dr. Hollozsy’s lab in laboratory rats with no effects noted. It is hypothesized that both the age of the ginseng root and the age of the final product are crucial for maintenance of glucose-lowering properties. It is generally accepted that the age of the root at the time of harvest should be at least 6 years old. However, similar guidelines for the age of the final product are not available. Most suppliers consider this information to be protected ‘proprietary information’ and therefore not released. Our preliminary information suggests that the potential glycemic benefits of ginseng are attenuated under inappropriate storage conditions is very important. This information suggests that ginseng may not be able to convey purported health benefits to the consumer unless specific storage conditions are maintained. Additionally, the human body’s ability to absorb and therefore utilize the ginseng is in question. Having found a supplier where the age of the root at the time of harvest and processing will be known, we will focus future efforts on absorption issues.
Based upon this information, absorption studies are currently underway in laboratory rats. Once there is a better understanding of absorption in humans, additional testing in humans, if warranted, may resume.
