Insulin resistance due to a defect distal to the insulin receptor: Demonstration in a patient with leprechaunism

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Abstract
A 2 yr old girl with acanthosis nigricans, glucose intolerance, marked hyperinsulinemia and somatic features characteristic of the leprechaunism syndrome was studied. Circulating plasma insulin levels were increased up to 50-fold and the patient showed a blunted hypoglycemic response to an injection of exogenous insulin (0.2 units/kg), indicating the presence of severe insulin resistance. Insulin purified from the patient''s plasma was normal on the basis of chromatographic, electrophoretic and immunologic criteria. Furthermore, the purified insulin competed effectively with 125I-labeled insulin for binding to insulin receptors on cultured IM-9 [human] lymphocytes and rat fat cells and also exhibited normal biological potency when tested on rat fat cells. Anti-insulin receptor and anti-insulin antibodies were not detected in the patient''s plasma, and plasma levels of glucagon, growth hormone and cortisol were normal. Insulin binding to the patient''s circulating mononuclear leukocytes was only slightly depressed into the low normal range and could not account for the severe insulin resistance. Studies on the patient''s fibroblasts revealed normal levels of insulin receptors but a total absence of insulin''s ability to accelerate glucose transport. Because rates of glucose transport and metabolism were normal in the basal state in the absence of insulin, it appears that this patient''s insulin resistance is apparently due to an inherited cellular defect in the coupling mechanism between occupied insulin receptors and the plasma membrane glucose transport system.