The activity of an insulin-degrading enzyme in soluble fractions of liver homogenate (“insulinase”) was compared with clearance of immunoreactive insulin (IRI) by cyclically perfused livers from normal, protein-depleted, and starved rats. Insulin disappearance from normal liver perfusates followed first-order kinetics, and clearances remained unchanged at levels between 1 and 5 nM insulin but fell at Insulin levels above 10 nM. At saturating concentrations (0.13 μM), the maximal rate of insulin removal was 12.5 pmol/mln./gm. wet liver, whereas the maximal degrading velocity of the “insulinase” fraction was 6.0 nmol/min./gm. wet liver. Furthermore, insulin clearance by the intact liver was not influenced by many substances affecting the “insulinase” system. Proinsulin (0.83 μM) acted as a competitive inhibitor, and glucagon, somatostatin, oxytocin, casein (all 1 to 6 μM), and Trasylol (2,000 K.I.U./ml.) inhibited “insulinase” noncompetitively. N-ethylmaleimide (1 mM) inhibited “insulinase” 100 per cent and partly delayed insulin removal from perfusates either because of concomitant reductions in oxygen consumption or because of incomplete titration of either accessible groups at active sites of insulin-degrading enzymes or cofactors.

When results were corrected for liver DNA, protein-depleted and starved rats, respectively, showed 80 per cent and 56 per cent of control “insulinase” activities (p < 0.005 and p < 0.005), but their intact livers cleared physiologic concentrations of insulin at similar.rates to those of controls. These differences, coupled with the lower saturability and probable higher affinity of the insulin removal process by the intact liver and the lack of inhibition of this process by “insulinase” inhibitors, suggest that the plasma membrane of the structurally preserved liver cell plays a physiologic role in the regulation of the rate of insulin catabolism either by degrading insulin itself or by limiting insulin delivery to degrading systems in the intracellular compartment.

This content is only available via PDF.