Resistin-like beta is a protein that in humans is encoded by the RETNLB gene. An infusion of either resistin or RELMB in rats rapidly induced severe hepatic but not peripheral insulin resistance. Increases in circulating resistin or RELMB levels markedly stimulated hepatic glucose production despite the presence of fixed physiologic insulin levels. This enhanced rate of glucose output was due to increased flux through glucose-6-phosphatase. The results supported the notion that a novel family of fat- and gut-derived circulating proteins modulates hepatic insulin action.