Quercetin selectively inhibits insulin receptor function in vitro and the bioresponses of insulin and insulinomimetic agents in rat adipocytes.

We report here that quercetin, a naturally occurring bioflavonoid, is an effective blocker of insulin receptor tyrosine kinase-catalyzed phosphorylation of exogenous substrate. The ID50 was estimated to be 2 +/- 0.2 microM in cell-free experiments, using a partially purified insulin receptor and a random copolymer of glutamic acid and tyrosine as a substrate. Insulin-stimulated autophosphorylation of the receptor itself was not blocked by quercetin (up to 500 microM). In intact rat adipocytes, quercetin inhibited insulin-stimulating effects on glucose transport, oxidation, and its incorporation into lipids. Inhibition of lipogenesis (50%) occurred at 47 +/- 4 microM, whereas full inhibition was evident at 110 +/- 10 microM quercetin. In contrast, the effect of insulin in inhibiting lipolysis remained unaltered in quercetin-treated adipocytes. The inhibitor was devoid of general adverse cell affects. Basal activities and the ability of lipolytic agents to stimulate lipolysis were not affected. Inhibition by quercetin enabled us to evaluate which insulinomimetic agents are dependent on tyrosine phosphorylation of endogenous substrates for stimulating glucose metabolism. Quercetin blocked lipogenesis mediated by insulin, wheat germ agglutinin, and concanavalin A. The lipogenic effect of Zn2+ and Mn2+ was partially blocked, whereas that of vanadate was not affected at all.(ABSTRACT TRUNCATED AT 250 WORDS)