Receptor-recycling model of clearance and distribution of insulin in the perfused mouse liver.
After perfusion of mouse livers with A14-125I-insulin for designated intervals, an acid-wash technique was employed to separately measure the surface-bound (Xs) and intracellular (Xi) A14-125I-insulin, as well as intracellular degradation products (Xdeg) of labelled insulin. From the perfusate concentrations (Cp) of A14-125I-insulin, the apparent intrinsic hepatic clearance of labelled insulin at a high dose (0.2 nmol/l) was shown to be 60% smaller than that at a low dose (0.018 nmol/l), indicating that the cellular uptake of insulin is remarkably nonlinear at the concentration range examined. From the time courses of Cp, Xs, Xi and Xdeg, the hepatic insulin disposition was shown to be largely accounted for by the receptor-mediated endocytosis. The observed data at the low dose were analysed to estimate biochemical parameters, (i.e., total receptor number, endocytotic rate constant and intracellular degradation rate constant) according to "receptor-recycling" and "non-receptor-recycling" models, using a computer-aided optimization procedure. The "receptor-recycling" model could not only adequately explain the Cp, Xs, Xi and Xdeg at the low dose, but also predict the Cp at the high dose. On the other hand, a "non-receptor-recycling" model, in which recycling of receptors was not assumed, could also explain the observed data at the low dose, but failed to predict the Cp at the high dose, indicating that the receptor recycling process is necessary to explain the hepatic insulin clearance at high insulin concentrations, at which hepatic insulin clearance should be limited by the rate of receptor recycling.(ABSTRACT TRUNCATED AT 250 WORDS)
Sato
H
H
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Terasaki
T
T
Mizuguchi
H
H
Okumura
K
K
Tsuji
A
A
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000493:pharmacokinetics; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008433:Mathematics; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D010477:Perfusion; D011972:Receptor, Insulin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics; D013552:Swine; D013997:Time Factors
D007328:Insulin; D011994:Recombinant Proteins; D011972:Receptor, Insulin