Previous studies have shown that flavonoids inhibit glucose uptake in cultured cells. In this report, we show that the grapefruit flavanone naringenin inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner. Naringenin acts by inhibiting the activity of phosphomositide 3-kinase (P13K), a key regulator of insulin-induced GLUT4 translocation. Although naringenin did not alter the phosphotyrosine status of the insulin receptor, insulin receptor substrate proteins, or P13K, it did inhibit the phosphorylation of the downstream signaling molecule Akt. In an in vitro kinase assay, naringenin inhibited P13K activity. A physiologically attainable dose of 6 muM naringenin reduced insulin-stimulated glucose uptake by approximately 20%. This inhibitory effect remained 24 h after the removal of naringenin from the culture medium. Collectively, our findings suggest that the regular consumption of uaringenin in grapefruit may exacerbate insulin resistance in susceptible individuals via impaired glucose uptake in adipose tissue. (C) 2003 Elsevier Science (USA). All rights reserved.