The present study was undertaken to investigate antihyperglycemic effects of Panax ginseng berry extract and ginsenoside Re in a type 2 diabetic ob/ob mouse model. In this obese insulin-resistant mouse model, obesity is due to a mutation in the obese gene that codes for leptin. Animals that are homozygous for the mutation exhibit morbid obesity and metabolic abnormalities that resemble type 2 diabetes in humans. The heterozygous littermates are lean and normoglycemic. Our results clearly demonstrate that Panax ginseng berry extract significantly improves glucose homeostasis. The fasting blood glucose levels started to decrease after 5 days of treatment and became completely normal by day 12. More importantly, the IPGTT results normalized after treatment. Dose-dependent antidiabetic effects of ginsenoside Re were also observed in ob/ob mice. Our results showed that lean littermate controls were not sensitive to the glucose-lowering effects caused by the extract and ginsenoside Re. This is the first report demonstrating that ginseng berry and ginsenoside Re can be used to treat diabetes.
The antidiabetic effect of ginseng root has recently been demonstrated. For instance, Kimura et al.  observed a notable fall in blood glucose levels 6 h after a single 90- mg/kg ginseng root extract IP dose in genetically obese diabetic KK-CAy mice. Vuksan et al.  demonstrated that 3 g American ginseng root given 40 min before the test meal significantly lowered blood glucose in nondiabetic subjects and type 2 diabetic patients. However, when studying a chronic disease such as diabetes, it is more pertinent to test the maintenance of lower blood glucose levels with long-term treatment rather than the acute hypoglycemic effect after a single dose. In this study, we measured fasting blood glucose 5 and 12 days after treatment. Unlike the short-term treatment study, we found that these compounds progressively reduced blood glucose levels in ob/ ob mice.
Prospective studies of populations at high risk for type 2 diabetes suggest that in most patients, the initial inherited defect is insulin resistance [31,32]. Insulin-stimulated in vivo glucose disposal is markedly reduced in patients with type 2 diabetes . In ob/ob mice, by 6 weeks of age, insulin resistance and hyperinsulinemia are well developed . In association with normalization of blood glucose levels, treatment with Panax ginseng berry extract in ob/ob mice also significantly reduced serum insulin concentration in both the fed and fasting states, indicating an improvement in peripheral insulin action. The insulin-sensitizing effect of the extract was further supported by our hyperinsulinemic-euglycemic clamp study.
Another possible action site for ginseng berry to exert its postprandial hypoglycemic effect is in the gastrointestinal tract. We previously reported that ginseng root extract, via gastric vagal afferents, inhibited brainstem neuronal activity . Others have reported that gastric secretion in vitro was inhibited by ginseng . These results suggest that ginseng may slow the digestion of food and decrease the rate of carbohydrate absorption. Chung et al.  recently showed that the antidiabetic effect of ginseng root could be attributed to blocking intestinal glucose absorption and inhibiting hepatic glucose-6-phosphatase activity.
Insulin resistance is often accompanied by obesity. Obesity not only increases the chance of developing type 2 diabetes, it is independently associated with insulin resistance and other morbidity . Thus, insulin resistance in obese type 2 diabetic patients is significantly worse than that in nonobese diabetic individuals . Therapeutic agents with both antidiabetic and anti-obese effects are therefore particularly beneficial. Our results show that ob/ob mice treated with Panax ginseng berry extract underwent a dose- and time-dependent reduction in body weight. Past studies have shown that insulin sensitivity in type 2 diabetic patients improves with weight loss , possibly because of an improvement in insulin-stimulated glucose transport into muscle . A similar mechanism may operate in the extract-treated ob/ ob mice to improve insulin resistance. The extract may exert its antidiabetic effect through actions that improve insulin sensitivity and the balance between food intake and energy expenditure. Because the antidiabetic effect of ginsenoside Re was achieved without an anti-obese effect, it is possible that weight reduction induced by Panax ginseng berry extract was not solely responsible for the hypoglycemic effect in ob/ ob mice. Future studies are required to identify compound(s) in the extract with anti-obese action.
The weight loss we observed after the extract treatment resulted in a 15% reduction in food intake and a 35% increased energy expenditure. Our results further support the latter by demonstrating a significantly higher body temperature in the extract-treated ob/ob mice, along with an increase in oxygen consumption. In patients with type 2 diabetes, calorie restriction, independent of weight loss, can improve insulin sensitivity . Obesity, hyperphagia, hypothermia, and reduced energy expenditure in ob/ob mice is due to a lack of leptin, which, in lean mice, signals hypothalamic centers on fat stores [28,40]. Whether the extract improve these defects by restoring hypothalamic control awaits further study. Past studies have shown that leptin also has a tendency to reduce body weight gain in lean mice [40,41]. We also observed a relative body weight reduction in extract-treated lean mice in our study.
In this study, we observed that Panax ginseng berry extract significantly reduces plasma cholesterol levels in ob/ob mice. Reduction of cholesterol levels by the extract may have an important clinical significance, since hyperlipidemia is often associated with type 2 diabetic patients.
The profile and concentrations of ginsenosides vary between ginseng root and berry, and this difference may contribute to the significant antihyperglycemic and/or anti-obese effects observed in our study. Panax ginseng berry contains a much higher concentration of ginsenoside Re than the root. We observed that ginsenoside Re has a significant antihyperglycemic activity without affecting body weight in ob/ob mice. Food intake and energy expenditure did not significantly change with ginsenoside Re. This suggests that other constituents in Panax ginseng extract have distinct pharmacological mechanisms that affect energy metabolism.
In summary, the present study demonstrated that administration of Panax ginseng berry significantly improved systemic insulin sensitivity and glucose homeostasis in ob/ ob mice. Our results support overall in vivo antihyperglycemic and anti-obese activity of the extract that may prove to be of clinical importance in improving the management of type 2 diabetes. In addition, the identification of a significant antihyperglycemic activity in ginsenoside Re may provide an opportunity to develop a novel class of antidiabetic agent.
The authors wish to thank Spring Maleckar for technical assistance.Funding information
This work was supported in part by the Tang Family Foundation, National Institutes of Health (NIH) Grants DK31842, DK44840, and AT00563, and an NIH Institutional Diabetes Research and Training Center grant.
HPLC, high-performance liquid chromatography; IP, intraperitoneal; IPGTT, intraperitoneal glucose tolerance test.
Address correspondence and reprint requests to Chun-Su Yuan, MD, PhD, Department of Anesthesia and Critical Care, University of Chicago Medical Center, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637. E-mail: cyuan@ midway.uchicago.edu.
Diabetes. 2002;51(6) © 2002 American Diabetes Association, Inc.
Y.-P.Z. is currently affiliated with Metabolex, Hayward, California; and K.S.P. is currently affiliated with the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Cite this: Antidiabetic Effects of Panax ginseng Berry Extract and the Identification of an Effective Component - Medscape - Jun 01, 2002.