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  • Title: Characterization of binding and phosphorylation defects of erythrocyte insulin receptors in the type A syndrome of insulin resistance.
    Author: Grigorescu F, Flier JS, Kahn CR.
    Journal: Diabetes; 1986 Feb; 35(2):127-38. PubMed ID: 3510919.
    Abstract:
    The type A syndrome of insulin resistance and acanthosis nigricans is characterized by severe insulin resistance due to a cellular defect in insulin action. To better understand the molecular nature of this defect, we have investigated insulin binding to circulating monocytes, erythrocytes, and the Triton X-100-solubilized erythrocyte receptor, and insulin-stimulated receptor autophosphorylation using cells and receptor from three type A patients. Insulin binding in both circulating cells and the soluble extract of erythrocytes indicated a heterogeneity of defects. Patients A1 and A2 both presented a major decrease in tracer insulin binding to intact cells and soluble insulin receptor. Determination of stoichiometric binding parameters using a cooperative model indicated that in patient A1 this was due to a reduction in the number of receptors, whereas in patient A2 the affinity constant for binding was decreased. Patient A3 presented near-normal insulin binding to erythrocytes and normal binding in intact monocytes, solubilized erythrocyte receptors, and cultured fibroblasts. Affinity labeling of erythrocyte receptor from this patient revealed a normal alpha-subunit and also a normal relative distribution of the higher-molecular-weight, nonreduced oligomeric forms of the receptor. Receptor autophosphorylation was measured using the solubilized insulin receptor from erythrocytes. The maximal stimulated phosphorylation was reduced by 79%, 76%, and 52% in patients A1, A2, and A3, respectively, relative to the simultaneous control. In all three patients, the autophosphorylation was stimulated only 1.0-3.5 times the basal level compared with controls, in which the stimulation was 5.7-fold +/- 1.2 (mean +/- 1 SD, P less than 0.005). In addition, in patients A1 and A2 a decrease in basal phosphorylation was observed and in patient A2 there was a rightward shift of the dose-response curve for insulin stimulation. These data and the correlation of coupling of receptor phosphorylation with the fractional occupancy of the receptor measured in the same extract suggest that these patients exhibit three types of defects. In patient A1, there is a loss in receptor number manifested by a parallel decrease in insulin binding and receptor phosphorylation. In patient A2, there is an additional decrease in the affinity constant leading to a decrease in both binding and receptor phosphorylation with an almost linear coupling between receptor occupancy and receptor phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)
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