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.