Alcohol Impacts on Central Regulation of Insulin Function; Potential Mechanism for GLP1 Reductions

Alcohol use disorder (AUD) affects ~28.6 million U.S. adults. Glucagon-like peptide-1 receptor (GLP1R) agonists, which increase plasma insulin, reduce alcohol (EtOH) intake in rodents, suggesting GLP1 may target insulin-regulatory pathways to reduce EtOH intake. Insulin regulates satiety and is disrupted by chronic EtOH intake, but whether disrupted insulin signaling is associated with increased EtOH intake is unknown. We hypothesized binge EtOH decreases insulin leading to an escalation of subsequent EtOH intake. To assess EtOH effects on insulin function, adult, male and female C57BL/6J mice underwent a 3-day binge EtOH exposure via the commonly used vapor-inhalation model or were air-exposed control mice and tested 4 hours following the last binge exposure. Binge EtOH significantly increased plasma glucose levels, decreased plasma insulin levels, and increased insulin immunoreactivity in pancreatic islets, suggesting binge EtOH sequesters insulin within the pancreas and reduces plasma insulin. To assess if insulin modulates EtOH intake, mice were trained to stably drink 15% EtOH in a two-bottle choice (2BC) procedure (8 sessions). Mice then underwent 3-day binge EtOH-vapor or air exposure and were retested for 2BC intake 4-hours post-binge. Binge EtOH significantly increased subsequent 2BC EtOH intake and preference compared to air controls. Intranasal insulin administration significantly decreased post-binge 2BC EtOH intake and preference compared to intranasal saline, suggesting insulin regulates EtOH intake. Similar results were observed following intraperitoneal administration of GLP1R agonist exendin-4. To elucidate underlying neurocircuitry, we expressed excitatory DREADDs in pancreatic-projecting brainstem vagal motor output neurons, a population of neurons known to express GLP1R and regulate insulin release. Chemogenetic activation of these neurons significantly decreased insulin sequestration, blood glucose levels, and EtOH intake. Collectively, these data suggest binge EtOH disrupts insulin signaling to promote subsequent EtOH intake, and that targeting mechanisms to promote insulin restoration, such as GLP1R or central circuits regulating insulin release, can reduce EtOH intake. NIH Grants AA026865 and AA031470 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.