We have evaluated the anti-diabetic effect of a alpha-glucan (MT-alpha-glucan) from the fruit body of maitake mushrooms (Grifola frondosa) on KK-Ay mice (a kind of genetical type 2 diabetes animal model). The effects of MT-alpha-glucan (450 or 150 mg kg (-1)) on diabetic mice were investigated by observing the changes in body weight, the level of fasting plasma glucose, glycosylated serum protein (GSP), hepatic glycogen, serum insulin, triglycerides, cholesterol, free fatty acid, liver superoxide dismutase (SOD), glutathione peroxidase (GSHpx), reduced glutathione (GSH) and malondialdehyde (MDA). Moreover, the binding capacity of insulin receptors on liver crude plasma membranes was assayed and histopathological changes in the pancreas were observed. Treatment with MT-alpha-glucan significantly decreased the body weight, level of fasting plasma glucose, GSP, serum insulin, triglycerides, cholesterol, free fatty acid and MDA content in livers. Treatment with MT-alpha-glucan significantly increased the content of hepatic glycogen, GSH and the activity of SOD and GSHpx. Moreover, the insulin binding capacity to liver crude plasma membranes increased and histopathological changes in the pancreas were ameliorated in the treatment group. These data suggest that MT-alpha-glucan has an anti-diabetic effect on KK-Ay mice, which might be related to its effect on insulin receptors (i.e., increasing insulin sensitivity and ameliorating insulin resistance of peripheral target tissues).