Individuals with only one allele for a functional insulin receptor have a tendency to hyperinsulinaemia but not to hyperglycaemia.

Recently, we described a leprechaun patient with a genetically transmitted severe insulin resistance due to the absence of functional insulin receptors as inferred from the loss of insulin binding to the patients' fibroblasts and the impaired autophosphorylation of the beta-chain of the receptor. This patient was homozygous for the genetic defect which was recently found to be a leucine to proline mutation at position 233 in the alpha-chain of the insulin receptor. In the present study we have examined insulin receptor functions in relatives of this patient. Some of these individuals are heterozygous for the genetic defect and have only one allele coding for a functional insulin receptor. Insulin binding to cultured fibroblasts from the heterozygous individuals is only 20-40% of control values indicating a Mendelian mode of inheritance of the binding defect. In contrast, insulin stimulated autophosphorylation of the beta-chain of the insulin receptor shows normal values, indicating compensation mechanisms operating on this process. The stimulation of the basal level of 2-deoxyglucose uptake by insulin in fibroblasts from the homozygous patient is 1.2 fold whereas the heterozygous and control individuals show stimulation values of approximately 1.65 fold. Basal levels of 2-deoxyglucose uptake are similar in these fibroblasts. Oral glucose tolerance tests on the heterozygous individuals indicate an increased requirement for insulin of the target tissues as concluded from the tendency towards hyperinsulinaemia with no observed hyperglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)