Insulin plays a key role in the stimulation of glucose uptake in tissues, such as muscle and adipocytes, as well as in the maintenance of glucose homeostasis. Impairment of insulin's ability to stimulate glucose uptake in the tissues is a major factor responsible for insulin resistance associated with type 2 diabetes.1) The primary mechanism of insulinstimulated glucose uptake in muscle and adipocytes is through the translocation of glucose transporter 4 (GLUT4) from intracellular pools to the plasma membrane.2) Insulin signal transduction is initiated by binding to the insulin receptor, followed by activation of the receptor tyrosine kinase (RTK).3,4) The activated RTK induces activation of downstream signaling pathways, such as phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. The translocation of GLUT4 to the plasma membrane was established to be mediated through the PI3K pathway, based on the use of pharmacological inhibitors, and expression of a dominant negative mutant or constitutively active form of PI3K. [5][6][7][8][9] Flavonoids, which are primarily phenylbenzo-g-pyrone (phenylchromone) derivatives, are polyphenolic compounds present in fruits, vegetables, and beverages.10) It has been reported that flavonoids possess a variety of biological activities, including anti-inflammatory, anti-oxidant, anti-bacterial, anti-cardiovascular disease, and anti-cancer activities.
11)These actions were suggested to result from changes in the activity of a number of intracellular enzymes, including tyrosine kinases, protein kinase C, PI3K, and MAPK. [11][12][13][14] The findings suggest that flavonoids may modify insulin-stimulated glucose uptake by modulating insulin RTK and/or PI3K activity in muscle or adipose cells. Indeed, several reports have shown that flavonoids, such as myricetin, quercetin, catechin-gallate, genistein, and naringenin, inhibited insulinstimulated glucose uptake in adipocytes. [15][16][17] However, the inhibitory mechanisms may be different for flavonoids of different classes or structures. Bazuine et al. 15) reported that genistein, an isoflavone, directly inhibited insulin-stimulated glucose uptake in mouse 3T3-L1 adipocytes. On the other hand, naringenin, a flavanone, inhibited insulin-stimulated glucose uptake through blocking PI3K activity in the cell line.17) Therefore, in this study, we investigated the effects of flavonoids on insulin-induced glucose uptake in mouse MC3T3-G2/PA6 adipocytes using a panel of 24 flavonoids, including flavones, flavonols, isoflavones, flavanones, flavanols and flavanonols.
MATERIALS AND METHODS
MaterialsThe flavones, flavone, apigenin, luteolin and chrysin, the flavonols, kaempferol, quercetin, rutin and morin, the isoflavones, daidzein and genistein, the flavanones, hesperetin, hesperidin and naringenin, the flavanonol, silybin, the flavanols, (ϩ)-catechin and EGCG, fetal bovine serum (FBS) and insulin were purchased from SigmaAldrich Corp. (St. Louis, MO, U.S.A.). The flavone, baicalein, and the flavonols, gal...
