Collectively, the data in the literature we present in this review suggest that plasma insulin clearance is reduced in people with obesity who are insulin resistant, not because of compensatory adaptations in tissues that clear insulin, but simply because both insulin action in and insulin clearance by tissues require insulin binding to its receptors and insulin receptors are downregulated in people who are insulin resistant. This evidence concerns the gene INSR and obesity due to melanocortin 4 receptor deficiency.