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Leprechaunism: In Vitro Insulin Action Despite Genetic Insulin Resistance

1987; Springer Nature; Volume: 22; Issue: 3 Linguagem: Inglês

10.1203/00006450-198709000-00010

1530-0447

Mitchell E. Geffner, Solomon A. Kaplan, Noelle Bersch, Barbara Lippe, W. G. Smith, R. Nagel, Thomas V. Santulli, Choh Hao Li, David W. Golde,

Transgenic Plants and Applications

ABSTRACT: We recently identified a female leprechaun infant with marked hyperinsulinemia [as high as 10,975/μU/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 by transforming the cells with the human retrovirus human T cell leukemia virus II. 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. The patient's I lymphoblasts, however, showed normal sensitivity to insulin-like growth factor I. In response to supraphysiologic insulin concentrations (25-1000 ng/ml), leprechaun T lymphoblasts showed significant augmentation of colony formation (peak 189% above baseline at 50 ng/ml); normal T lymphoblasts also showed responsiveness at these high insulin concentrations. Preincubation with a monoclonal antibody against the insulin-like growth factor I receptor (αIR-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 T 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.