Some patients with severe
insulin resistance develop pathological tissue growth reminiscent of
acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of
insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of
phosphoinositide 3-kinase (PI 3-kinase) is considered essential for
insulin's metabolic signaling, we have examined
insulin-stimulated
PI 3-kinase activity in anti-
insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of
insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated
PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the
insulin receptor, IRS-1, or p85alpha.
Insulin stimulation of mitogenesis in PA fibroblasts, as determined by
thymidine incorporation, was indistinguishable from controls, as was
mitogen-activated protein kinase phosphorylation, confirming the integrity of
insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor
insulin signaling in the PA subtype of
insulin resistance, which involves impairment of the activation of
PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo
hyperinsulinemia activating intact mitogenic signaling pathways emanating from the
insulin receptor.