125I-insulin: kinetics of interaction with its receptors and rate of degradation in vivo

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Abstract
I.v. injected [125I]monoiodoinsulin (125I-Tyr-insulin) was mainly taken up by the kidney and by the liver. To focus on the saturable mechanisms pertaining to plasma insulin clearance, the following experiments were performed on fed, Nembutal-anesthetized and nephrectomized rats. Following i.v. injection of 125I-Tyr-insulin alone, the apparent distribution space of the tracer was 100 ml/100 g body wt. The concomitant injection of saturating amounts of insulin (4 U [unit]) reduced the tracer''s distribution space to 20 ml/100 g. Following i.v. injection of 125I-Tyr-insulin alone, liver uptake of radioactivity was rapid and important. After the 3rd min, liver radioactivity decreased with a half-life of 6.5 min. The concomitant injection of 4 U native insulin markedly reduced liver radioactivity and altered its time course. Following sequential injection of 125I-Tyr-insulin at time 0 and an excess of native insulin at time t, liver radioactivity briskly decreased, but not to the level achieved by the concomitant injection of 125I-Tyr-insulin plus insulin; some radioactivity was irreversibly bound to the liver. Within 2 min, the radioactivity released by exogenous insulin reappeared in the plasma as intact 125I-Tyr-insulin. The amount of 125I-Tyr-insulin reversibly bound to the receptor compartment decreased with a half-life of 4 min. 125I- was the major radioactive breakdown product of 125I-Tyr-insulin that reentered the plasma. Production of 125I- was markedly reduced by saturation of the insulin degrading mechanisms or of dehalogenase activity. In the former case, 125I-Tyr-insulin remained undamaged in the plasma. In the latter case, 125I-Tyr was produced instead of 125I-. As estimated by 125I- production rate, 125I-Tyr-insulin degradation was initiated shortly after monoiodoinsulin injection and completed within .+-. 10 min. Of the extrapancreatic insulin 4/5 was bound to the liver and peripheral tissues. On a functional basis, 2 cellular subcompartments were defined, one in reversible equilibrium with the plasma and which contains 125I-Tyr-insulin (receptor) and another not in equilibrium with the plasma and probably concerned with 125I-Tyr-insulin degradation.