Normal metabolism is characterized by an appropriate relationship between insulin resistance and plasma insulin levels. The quality of this interrelationship is defined by the Disposition Index, which has been considered a measure of the ability of the pancreatic β-cells to compensate for insulin resistance. Recently however it has become clear that an additional mechanism of compensation is alterations in insulin clearance mechanisms. In fact, liver clearance and extrahepatic clearance mechanisms are differentially regulated, revealed in evidence that hepatic but not extrahepatic insulin clearance is reduced in certain at risk populations including African Americans and Hispanic Americans. The goal of this proposal is to perform experiments in animals to elucidate the relationship between β-cell compensation for insulin resistance versus compensation at the level of insulin clearance at hepatic versus extrahepatic loci. We propose to examine two mechanisms of inducing insulin resistance – high fat diet, and treatment with the insulin receptor antagonist S961. The relative roles and mechanisms of β-cell upregulation and clearance down-regulation will be examined. Additionally, this relationship will be examined in a model of prediabetes to determine if there is coordination between compensation mechanisms. Additionally we will examine the effects of reducing liver clearance with the CEACAM1 antisense oligonucleotide to examine whether reduced clearance per se can contribute to the pathogenesis of diabetes. Finally, the relative importance and mechanisms of β-cell compensation and alteration in insulin clearance will be examined in pregnant animals which display possibly the most profound physiologic manifestation of hyperinsulinemia in the face of extreme insulin resistance. These studies will determine if changes in clearance of insulin at hepatic versus extrahepatic sites could be important targets to replace β-cell proliferation to maintain normal metabolic function despite profound insulin resistance.