In advanced alcohol-related liver disease, hepatic insulin signaling is impaired at the level of IGF-1 receptor and IRS-1 phosphorylation, despite increased receptor expression and preserved downstream Akt activation, suggesting compensatory pathways may maintain survival signaling despite upstream resistance.

Alcohol causes fat molecules called ceramides to build up in liver cells, which stresses the internal factory that makes proteins. This stress blocks the first signals from insulin and IGF-1 receptors by tagging a key messenger with a chemical group that stops it from working. Even though the receptors themselves increase in number, the signal cannot pass through. However, a separate survival pathway stays active, keeping the cell alive despite the broken signal. This happens because the stress also triggers a backup system that keeps the survival signal running, even when the main signal is broken.