Objective: The water-soluble extract of Ganoderma lucidum mycelia (WER) is prepared from a solid medium composed of bagasse and rice bran overgrown with Ganoderma lucidum mycelia. Recently, we reported that WER shows a blood glucose-lowering effect in maltose-loaded non-diabetic mice. Here, we investigated the efficacy of WER in type 2 diabetic state using KK-A^y mice. Moreover, the food-drug interactions of WER with α-glucosidase inhibitors, voglibose or acarbose were examined using both in vitro and in vivo experiments.
Methods: The glucose-lowering effects of oral administration in vivo of WER alone, or concomitant administration of WER with voglibose/acarbose on the elevation of blood glucose levels by sugar-tolerance tests were examined in KK-A^y mice. The inhibitory effects on α-glucosidase in vitro were also evaluated.
Results: Oral administration of WER (1 g/kg), which did not affect fasting blood glucose, significantly suppressed the hyperglycemia after loading of maltose (18% of decrease in AUC) compared to the water-administrated control mice. In vitro study showed that WER inhibited maltase in concentration-dependent manner. The inhibitory effects of lower concentrations of voglibose or acarbose on α-glucosidase activity were additively enhanced by the presence of WER, but those of higher concentrations were not affected. The glucose-lowering effect of voglibose (0.1 mg/kg) disappeared in maltose-loaded KK-A^y mice when the drug was concomitantly administrated with WER (1 g/kg), whereas acarbose (16 mg/kg) with WER showed no significant change in its effect.
Conclusion: These results demonstrated that WER shows the glucose-lowering effect in maltose-loaded KK-A^y, which may be based on inhibition of the α-glucosidase activity. The present study suggests that concomitant intake of WER with voglibose may override the therapeutic effect of voglibose on postprandial hyperglycemia by food-drug interaction in diabetic state.

Objective: The water-soluble extract of Ganoderma lucidum mycelia (WER), which is used as a health food, reduced hyperglycemia and enhanced glucose transporter 4 (GLUT4) translocation to the plasma membrane in skeletal muscle and adipose tissue in KK-A^y mice, a type 2 diabetic animal model with obesity.In order to elucidate the reduction of hyperglycemia by WER, we investigated the translocation of glucose transporter 4, glucose uptake and associating signal transduction in rat skeletal muscle (L6) cells. Method: The glucose uptake was analyzed with radioactive 2-deoxy-D-glucose.The localization of GLUT4 in L6 cells treated with various concentrations of WER was analyzed with immunohistochemical staining and Western blot technique.As a positive control, insulin or troglitazone was used in these experiments.Furthermore, the activation of intracellular signaling pathways by Western blot analysis and the influence of glucose uptake using four kinds of inhibitors (LY294002 as potent PI3K inhibitor, rapamycin as mTOR inhibitor, Gö6983 as broad PKC inhibitor, compound C as AMPK inhibitor) was evaluated. Results: GLUT4 protein content in the plasma membrane was induced in a dose-dependent manner of WER without increasing the gene expression and amount of total protein in the L6 cells and the glucose uptake was augmented with increasing the amount of GLUT4 translocated on the plasma membrane.The phosphorylation of phosphatidylinositol-3 kinase (PI3K), Akt and acetyl CoA carboxylase (ACC) were induced in a concentration dependent manner and inhibited by the above inhibitors except rapamycin. Conclusion: These results indicate that the hypoglycemic effect of some material(s) in WER may be due to the enhancement of glucose uptake through GLUT4 translocation on the plasma membrane by activating the PI3K/Akt pathway through improving insulin resistance.