LEPRECHAUNISM - STUDIES OF THE RELATIONSHIP AMONG HYPERINSULINISM, INSULIN RESISTANCE, AND GROWTH-RETARDATION

The syndrome of leprechaunism, characterized by severe intrauterine growth retardation, postnatal growth failure, abnormal facies, and a variety of other abnormalities, was studied in a female infant. The patient, who had hyperglycemia and glycosuria, was found to have markedly elevated serum concentrations of immunoreactive insulin, hyperplasia of the β-cells of the islets of Langerhans, and unresponsiveness to exogenous insulin. Studies were undertaken to determine the mechanism (s) for her insulin resistance and to investigate the relationship between insulin resistance and growth failure. Her circulating insulin appeared to be chemically and biologically normal since it behaved like purified crystalline insulin in RIA and in a placental cell competitive membrane-binding assay for insulin, the elution pattern on gel chromatography was typical of endogenous insulin in serum, the kinetics of its in vitro degradation by insulin glucagon protease were normal, and it exhibited normal biological activity in in vitro assays using isolated adipocytes. No evidence for antagonism of insulin action by cortisol or GH was found and no circulating antibodies to insulin or cell membrane insulin receptors were detected. Cultured fibroblasts from the patient were capable of binding insulin in a manner similar to fibroblasts grown from normal infants. This is interpreted as evidence that her hyperinsulinism did not result from a primary reduction in insulin receptors. A reduction in specific insulin binding was observed with membranes prepared directly from the patient's liver. This was interpreted as evidence of downregulation of insulin receptors secondary to her marked hyperinsulinism. Unlike control fibroblasts, addition of high concentrations of insulin or serum to the patient's serum-starved, cultured fibroblasts failed to stimulate their incorporation of [methyl-3H]thymidine. This finding, taken with those which exclude a variety of other possible mechanisms which might explain the patient's hyperinsulinism and insulin resistance, makes it tempting to speculate that the primary defect is an intracellular refractoriness to insulin action. © 1979 by The Endocrine Society.