Acute effects of ethanol on hepatic endocytosis and processing of insulin in perfused rat liver.
This study utilizes the perfused rat liver combined with subcellular fractionation and compartmental analysis to investigate the effects of ethanol on hepatic uptake, endocytosis, and processing of insulin. At 4 min after the start of a 2-min pulse of radiolabeled insulin, increasing ethanol concentrations progressively inhibited insulin uptake by the liver (57% at 50 mM ethanol). Subcellular fractionation of the perfused livers showed a progressive shift in distribution from a predominantly endosomal location (control) to a bimodal distribution between endosomes and plasma membrane. This could be largely accounted for by a specific reduction in the endosome-associated insulin. Binding studies showed no changes in the binding properties of the plasma membrane insulin receptor. Compartmental analysis of the perfusate efflux curves confirmed the lack of effect of ethanol on the binding constants but showed a significant decrease in the endocytic rate constant (50%) together with an increase in the retroendocytic rate constant (33%). Simulation studies with the compartmental model showed that these changes could account for the observed decrease in uptake by the liver. No changes were found in the subsequent endocytic degradation of insulin.
Fawcett
J
J
Endocytosis Research Group, Medical Research Council Clinical Research Centre, Harrow, Middlesex, United Kingdom.
Hammond
B
B
Smith
G D
GD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions
D007328:Insulin; D000431:Ethanol; D005947:Glucose