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Tyrosine-Kinase Defect of the Insulin Receptor in Cultured Fibroblasts from Patients with Lipoatropic Diabetes^*

Laboratory of Cell Biology INSERM U181, Saint Antoine Faculty of Medicine 75012 Paris
Department of Endocrinology and Metabolic Diseases, Lapeyronie Hospital
CRBM CNRS LP 80402/INSERM U249, University of Montpellier I Montpellier, France
Research Division and Department of Medicine, Joslin Diabetes Center, Harvard Medical School Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Dr. Jacqueline Capeau, Laboratory of Cell Biology, INSERM U181, Saint Antoine Faculty of Medicine, 27 rue Chaligny, 75012 Paris, France.

Postbinding defects in insulin action were described previously in cultured fibroblasts from six patients with lipoatropic diabetes. To define the contribution of the insulin receptor tyrosine kinase in these defects, we studied autophosphorylation and kinase activity of lectin purified receptors from these six patients and six normal cell lines. The patients' insulin receptors, prepared by precipitation with polyethylene glycol, had normal insulin binding characteristics and autophosphorylation properties, but a 56% decrease in the tyrosine kinase activity toward an exogenous substrate. To identify more subtle qualitative defects in autophosphorylation, insulin receptors were sequentially immunoprecipitated and analyzed for their phosphoaminoacid content. The phosphorylated receptors precipitated with an antiphosphotyrosine antibody contained labeled phosphotyrosine, whereas those in the supernatant, when further precipitated with an antireceptor antibody, contained only phosphoserine. Under these conditions, the insulin-stimulated autophosphorylation of tyrosine was significantly decreased by 54% in the patient receptors compared to normal subjects' receptors. In addition, insulin-like growth factor-I stimulation of autophosphorylation of its receptor was reduced by 59% in the patients' cells compared to those from normal subjects. We conclude that fibroblasts from patients with lipoatropic diabetes have defects in the tyrosine kinase activity of their insulin and their insulin-like growth factor-I receptors that might give rise to the in vitro hormone resistance and be related to the in vivo hormone resistance that occurs in these patients.

^* This work was supported by INSERM Grants U.181 and CRE 87006 and grants from the Saint Antoine Faculty of Medicine.

Received November 6, 1988.

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