ABSTRACT: Ginseng and its active component, ginsenoside Re, are popular herbal products that are advocated for treatment of diabetes. The purpose of this study was to determine whether ginseng or ginsenoside Re improves ?-cell function and insulin sensitivity (IS) in insulin-resistant subjects.Overweight or obese subjects (BMI = 34 ± 1 kg/m²) with impaired glucose tolerance or newly diagnosed type 2 diabetes were randomized to 30 days of treatment with ginseng root extract (8 g/day), ginsenoside Re (250-500 mg/day), or placebo. ?-Cell function was assessed as the disposition index (DI) and measured by a frequently sampled oral glucose tolerance test, and IS was assessed as the relative increase in glucose disposal during a hyperinsulinemic-euglycemic clamp procedure plus stable isotope tracer infusion.Values for DI and IS after therapy (Post) were not different from values before therapy (Pre) in the placebo (DI: Pre, 5.8 ± 0.9 × 10?³ and Post, 5.8 ± 0.8 × 10?³, P = 0.99; IS: Pre,165 ± 29% and Post, 185 ± 24%, P = 0.34), ginseng (DI: Pre, 7.7 ± 2.0 × 10?³ and Post, 6.0 ± 0.8 × 10?³, P = 0.29; IS: Pre, 171 ± 72% and Post,137 ± 59%, P = 0.88), and ginsenoside Re (DI: Pre, 7.4 ± 3.0 × 10?³ and Post, 5.9 ± 1.1 × 10?³, P = 0.50; IS: Pre, 117 ± 31% and Post, 134 ± 34%, P = 0.44) groups. Ginsenosides Re, Rb?, and Rb? were not detectable in plasma after treatment with ginseng root extract or ginsenoside Re.Oral ginseng or ginsenoside Re therapy does not improve ?-cell function or IS in overweight/obese subjects with impaired glucose tolerance or newly diagnosed diabetes. Poor systemic bioavailability might be responsible for the absence of a therapeutic effect.