Differences Between Insulin Degradation by Soluble Fractions and Insulin Clearance by Perfused Livers of Normal, Protein-depleted, and Starved Rats

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Abstract
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 1st-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 .mu.M), the maximal rate of insulin removal was 12.5 pmol/min/g wet liver, whereas the maximal degrading velocity of the insulinase fraction was 6.0 nmol/min per g wet liver. Insulin clearance by the intact was not influenced by many substances affecting the insulinase system. Proinsulin (0.83 .mu.M) acted as a competitive inhibitor, and glucagon, somatostatin, oxytocin, casein (all 1-6 .mu.M) and Trasylol inhibited insulinase noncompetitively. N-ethylmaleimide (1 mM) inhibited insulinase 100% and partly delayed insulin removal from perfusates either because of concomitant reductions in O2 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% and 56% 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 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.