Background:The role of the ubiquitin-proteasome pathway under high glucose conditions is unclear. Results: AMPK␣2 interacts with WWP1, and its expression is down-regulated by the ubiquitin proteasome pathway in high glucose culture conditions in C2C12 cells. Conclusion: WWP1 down-regulates AMPK␣2 expression through direct interaction in high glucose culture conditions of skeletal muscle C2C12 cells. Significance: The ubiquitin proteasome pathway may involve high glucose-induced AMPK␣2 down-regulation.