AJP - Gastrointestinal and Liver Physiology, Vol 261, Issue 2 199-G205, Copyright © 1991 by American Physiological Society
Impairment of hepatic insulin receptors during chronic ethanol administration
B. C. Patel, C. D'Arville, M. Iwahashi and F. R. Simon
Hepatobiliary Research Center, University of Colorado School of Medicine, Denver 80262.
Chronic alcoholism is frequently associated with impaired intermediary
metabolism and insulin resistance. The cellular defects leading to insulin
resistance have not been clearly defined but could result from reduced
insulin binding or abnormalities in any one of several postreceptor steps.
The purpose of the present studies was to measure 125I-insulin binding and
internalization kinetics and postreceptor response of the enzyme activity
of tyrosine aminotransferase in isolated cultured rat hepatocytes. Four
weeks of alcohol ingestion significantly reduced to 47% of control the
125I-insulin binding sites measured either as surface or total (after
digitonin permeabilization). In contrast, 125I-epidermal growth factor
binding was not significantly changed. Internalization of surface-bound
125I-insulin was decreased, but degradation was not increased, indicating
that altered kinetics did not account for the change. Ethanol ingestion
markedly reduced in liver cytosol some enzymes regulated by insulin and
involved in glucose homeostasis. Basal activities of tyrosine
aminotransferase and glucokinase were reduced 51% (P less than 0.01) and
32% (P less than 0.01), respectively. In contrast, phosphoenolpyruvate
carboxykinase was unchanged. In short-term cultured hepatocytes from
ethanol-fed rats, the maximum response of tyrosine amino-transferase to
insulin was reduced 40% (P less than 0.01) without a change in the
concentration causing 50% of the maximum response (EC50) compared with
controls. In contrast, dexamethasone increased tyrosine aminotransferase to
similar maximal levels and with similar EC50, indicating that ethanol did
not alter the intracellular response. In conclusion, chronic ethanol
ingestion caused significant time-dependent and selective changes in cell
surface binding of insulin that was associated with subsequent postreceptor
events.
