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ABSTRACT. We recently identified a female leprechaun infant with marked hyperinsulinemia [as high a s 10,975 pU/ml (78,746 pmol/liter)], presumably secondary to insulin resistance. She had two physical findings suggestive of possible insulin action: cystic ovarian enlargement with gonadotropin-independent steroid secretion and persistent, severe myocardial hypertrophy. To examine the pathophysiology of this disorder we measured the in vitro sensitivity to insulin and other growth factors of erythroid progenitors and a T-lymphoblast cell line derived from her peripheral blood. Resistance to insulin was demonstrated by failure of her circulating erythroid progenitor cells to augment proliferation in response to physiologic concentrations of insulin (1-10 ng/ml). An immortalized T lymphoblast cell line was established bv transforming the cells with the human retrovirus human"I' cell leukemia virus 11. This cell line showed little or no response to physiologic concentrations of insulin contrary to consistently observed stimulation of colony formation by cell lines similarly derived from normals. 'l'he patient's 'I' lymphoblasts, however, showed normal sensitivity to insulin-like growth factor I. I n responsc to supraphysiologic insulin conccntrations (25-1000 ng/ml), leprechaun 'I' lymphoblasts showed significant augmentation of colony formation (peak 189% above baseline a t 50 ng/ml); normal 'I' lymphoblasts also showed responsiveness at these high insulin concentrations. Preincubation with a monoclonal antibody against the insulin-like growth factor I receptor (uIK-3 at 5000 ng/ml) blocked the in vitro effect of physiologic concentrations of insulin-like growth factor and supraphysiologic concentrations of insulin on leprechaun and control 1' lymphoblast colony formation, but had no clear effect upon the response to physiologic insulin concentrations. These findings document genetic insulin resistance in hematopoietic cells from a patient with leprechaunism. Response to supraphysiologic concentrations of insulin appears to be mediated via the insulin-like growth factor receptor mechanism which remains intact. Such action in vivo could account for the ovarian and cardiac findings in the patient.

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