IMPAIRED ACTIVATION OF PHOSPHOINOSITIDE 3-KINASE BY INSULIN IN FIBROBLASTS FROM PATIENTS WITH SEVERE INSULIN-RESISTANCE AND PSEUDOACROMEGALY - A DISORDER CHARACTERIZED BY SELECTIVE POSTRECEPTOR INSULIN-RESISTANCE

Some patients with severe insulin resistance develop pathological tiss ue growth reminiscent of acromegaly, Previous studies of such patients have suggested the presence of a selective postreceptor defect of ins ulin signaling, resulting in the impairment of metabolic but preservat ion of mitogenic signaling, As the activation of phosphoinositide 3-ki nase (PI 3-kinase) is considered essential for insulin's metabolic sig naling, we have examined insulin-stimulated PI 3-kinase activity in an ti-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 w as reduced markedly in fibroblasts from the PA patients (32 +/- 7% of the activity of normal controls, P < 0.01), Genetic and biochemical st udies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS- 1, or p85 alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, con firming the integrity of insulin's mitogenic signaling pathways in thi s condition. These findings support the existence of an intrinsic defe ct of postreceptor insulin signaling in the PA subtype of insulin resi stance, which involves impairment of the activation of PI 3-kinase, Th e PA tissue growth seen in such patients is likely to result from seve re in vivo hyperinsulinemia activating intact mitogenic signaling path ways emanating from the insulin receptor.