Chronic hyperinsulinemia accelerates hepatocyte senescence, driving progression of non-alcoholic fatty liver disease in patients with obesity and type 2 diabetes. Findings presented at EASD 2025 show that GLP-1 receptor agonists, including Exendin-4 and GLP-1, can counteract this effect and reduce cellular aging in liver cells.

In the study, human hepatocytes exposed to sustained high insulin levels were treated with Exendin-4 or GLP-1. Both treatments significantly decreased senescence markers such as ZMAT3, p53, p21, and phosphorylated γH2AX. Additionally, pro-inflammatory senescence-associated secretory factors, including IL8, IL18, and MMP3, were reduced. Mechanistic studies suggested that activation of AMPK underlies these anti-senescence effects. Both agents also downregulated DPP4, preserving their activity in hyperinsulinemic conditions.

These results indicate that GLP-1 receptor agonists may provide a novel therapeutic approach to managing fatty liver disease by targeting hepatocyte senescence, beyond their traditional role in glucose regulation.