Influence of Changes in Insulin Receptor Binding during Insulin Infusions on the Shape of the Insulin Dose-Response Curve for Glucose Disposal in Man*

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Abstract
To determine the influence of insulin infusions used in dose-response studies on monocyte insulin binding, monocyte insulin binding and glucose disposal were measured in six normal subjects before and at the end of each of four sequential 2-h insulin infusions (0.4, 1.0, 2.0, and 10 mU kg−1 min−1). Monocyte insulin binding was unaltered at the end of the first three infusions (plasma insulin, 31 ± 2 (SEM),77 ± 3, and 184 ± 10 μU/ml) but was decreased after the last infusion (plasma insulin, 1730 ± 125 μU/ml) at 0.2 through 10.2 ng/ml insulin concentrations in the binding assay (P < 0.01). Using a one-site model, this could be ascribed to a decrease in insulin receptor affinity (1.54 ± 0.26 vs. 2.27 ± 0.48 × 108 M−1 P < 0.05), whereas in a two-site model this appeared to be due to a decrease in high affinity binding sites (1,868 ± 228 vs. 2,387 ± 207, P < 0.02). Nevertheless, insulin receptor occupancies estimated to occur during the insulin infusions were virtually identical whether preinsulin infusion binding data (745 ± 72, 1,383 ± 117, 2,572 ± 302, and 10,092 ± 1,708) or binding data at the end of each infusion (702 ± 56, 1,367 ± 150,2,383 ± 318, and 9,158 ± 2,023) were used to calculate occupancy. These results ndicate that although monocyte insulin binding decreased during dose-response experiments using sequential infusions of insulin, due to the concentrations of insulin at which this occurs this decrease did not alter the shape of the dose-response curve relating glucose disposal to monocyte insulin receptor occupancy.

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