Extreme Insulin Resistance in Association with Abnormally High Binding Affinity of Insulin Receptors from a Patient with Leprechaunism: Evidence for a Defect Intrinsic to the Receptor

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Abstract
Previously, we have identified novel abnormalities in insulin binding to cultured lymphocytes from a patient (leprechaun/Ark-1) with a genetic form of extreme insulin resistance. Insulin receptors from this patient are characterized by abnormally high affinity for insulin as well as markedly decreased sensitivity to alterations in pH and temperature. In the present report, we describe further studies investigating the mechanism of the binding abnormalities in this patient. The binding abnormalities persist after solubilization of insulin receptors from lymphocyte plasma membranes. The apparent binding affinity of the insulin receptor from leprechaun/ Ark-1 is 2- to 3-fold higher than observed with receptors from normal subjects. In addition, the solubilized insulin receptor from leprechaun/Ark-1 is markedly less sensitive to alterations in the pH. In further studies, insulin receptors were partially purified by affinity chromatography over wheat germ agglutinin-agarose. With normal insulin receptors, lectin affinity purification leads to an approximately 3-fold increase in the binding affinity of insulin. In contrast, with insulin receptors from leprechaun/Ark- 1, no such increase in binding affinity is observed. As suggested by previous studies, the increase in the binding observed subsequent to lectin affinity purification may result from removal of the influence of an affinity regulator. With normal insulin receptors, the interaction between the affinity regulator and the receptor has an inhibitory effect on the binding affinity for insulin. With receptors from leprechaun/Ark-1, the absence of an effect of wheat germ agglutinin-agarose suggests that the receptor defect in that patient may be associated with a defective interaction between the receptor and the affinity regulator. Despite the abnormalities in the binding functions of the solubilized insulin receptors from leprechaun/Ark-1, direct studies of receptor structure did not identify any structural defect. The molecular weight as well as the subunit structure of the detergent-solubilized insulin receptors from leprechaun/Ark-1 appeared normal as judged by gel filtration chromatography. Although the abnormal binding studies with solubilized receptors from leprechaun/Ark-1 strongly suggest an intrinsic abnormality in the structure of the receptor, the presently available techniques do not allow for direct demonstration of the presumed structural defect. J Clin Endocrinol Metab55: 1108, 1982)

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