Insulin initiates its action by interacting with specific receptors on the plasma membrane of target cells. Mutations in these receptors cause the inherited insulin-resistant syndrome leprechaunism. Affected patients have severe intrauterine and post-natal growth restriction coupled with severe metabolic abnormalities. Fibroblasts from patients with leprechaunism have impaired in vitro growth, reflecting the growth restriction seen it in vivo. To determine the reason for the defective growth of cells from patients with mutant insulin receptors, gene expression was compared among fibroblasts from controls and patients with leprechaunism using DNA microarrays. Of the 12,626 human genes tested, cells from patients with leprechaunism had consistently increased mRNA for 151 genes and decreased mRNA for 51 genes. The level of expression of selected genes was independently confirmed by real time RT-PCR. Leprechaun cells had increased expression of several genes involved in metabolic functions, several of which were not previously known to be regulated by the insulin receptor. The absence of insulin receptors modified the expression of genes controlling apoptosis and cellular growth. Functional analysis indicated that cells from patients with leprechaunism had a normal response to apoptotic stimuli when mitochondrial potential and caspase activity were assayed. About 20% of the genes whose RNA was decreased in leprechaun cells coded for proteins involved in cell growth and differentiation. These results suggest that the insulin receptor is a physiologic regulator of several genes involved in intermediate metabolism even in human fibroblasts. Decreased expression of growth-promoting genes may explain the growth restriction of patients with severe insulin resistance.