Impairment of hepatic insulin receptors during chronic ethanol administration.
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.
Hepatobiliary Research Center, University of Colorado School of Medicine, Denver 80262.
B C
BC
Patel
C
C
D'Arville
M
M
Iwahashi
F R
FR
Simon
D000818:Animals; D001665:Binding Sites; D002470:Cell Survival; D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014444:Tyrosine Transaminase / Q000378:metabolism
D007328:Insulin; D000431:Ethanol; D014444:Tyrosine Transaminase; D005941:Glucokinase; D011972:Receptor, Insulin; D010729:Phosphoenolpyruvate Carboxykinase (GTP)