A Postbinding inhibitor of insulin action: Increased concentrations in the plasma of non-insulin-dependent diabetic subjects
1984
Dean, Brian | Peluso, Ivana | Harrison, Len C.
Extract: "Postreceptor" insulin resistance in persons with non-insulin-dependent diabetes (NIDDM) could be due to an intrinsic defect in insulin-sensitive pathways or to the action of a circulating inhibitor. Since evidence for the former is lacking, we have addressed the question of a circulating inhibitor by examining the effect of plasma and plasma extracts from NIDDM subjects on the lipogenic response of rat adipocytes to insulin. A majority (77%) of plasma samples (1:20 dilution) from unselected, treated NIDDM subjects (N=69) inhibited insulin-stimulated conversion of H-3-labeled glucose to H-3-labeled lipid in rat adipocytes to a greater extent than did control samples (N=24). The mean SD inhibition by NIDDM plasma was significantly greater than by control plasma. Diabetic and, to a lesser degree, control plasma both caused a significant decrease in the maximal response of lipogenesis to insulin. Inhibitory activity was extracted into acid/ethanol, present in the flow of a Sep-pak C18 column, heat-stable (56 degrees C for 30 min (plasma), 80 degrees C for 30 degrees min (acid/ethanol)), resistant to proteases, and dialyzable through 1000-dalton-mol wt exclusion dialysis tubing. The inhibition by NIDDM plasma or partially purified inhibitor could not be explained by the presence of insulin antibodies, insulin receptor antibodies, other inhibitors of insulin binding, or the concentrations of known counterregulatory factors. There was no correlation between inhibitory activity and plasma glucose. Our findings suggest that a humoral inhibitor of postreceptor insulin action is present in increased concentrations in the plasma of NIDDM subjects. The nature of this inhibitory activity and its pathophysiologic significance deserves further investigation. (Author)
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