Tirzepatide improves pancreatic β-cell function in mice and patients with type 2 diabetes

ABSTRACT The dual incretin receptor agonist tirzepatide improves β-cell function in T2D patients, but the underlying mechanism remains unclear. This study aimed to elucidate the molecular pathway through which tirzepatide restores β-cell functional improvement. High-fat diet (HFD)-fed C57BL/6J mice were treated with vehicle, a GIP analogue, semaglutide or tirzepatide. Tirzepatide significantly reduced body weight and improved glucose tolerance in HFD-fed mice without altering β-cell mass, proliferation, or apoptosis. Instead, tirzepatide reversed β-cell dedifferentiation, as indicated by reduced ALDH1A3 expression and restored levels of the identity transcription factors PDX1 and MAFA. Single-cell RNA sequencing (scRNA seq) and in vitro studies revealed that tirzepatide up-regulated FOXO1, reactivating the FOXO1-PDX1/MAFA axis. In T2D patients, tirzepatide improved glycemic control, reduced insulin demand, increased HOMA-β, and decreased HOMA-IR. Improvement in HOMA-β correlated positively with baseline insulin resistance. Hence, our study suggested that tirzepatide restores β-cell function in T2D by reprogramming stressed β cells and re-establishing β-cell identity through FOXO1-dependent transcriptional reactivation. These findings provide a mechanistic basis for the superior efficacy of dual incretin receptor agonism in T2D management. ARTICLE HIGHLIGHTS Tirzepatide restores β cell identity and function without altering β cell mass in HFD induced diabetic mice. Tirzepatide reverses β-cell dedifferentiation and restores key β-cell transcription factors (PDX1, MAFA) through reactivation of the AKT-FOXO1 signaling pathway. Tirzepatide increases HOMA-β and decreases HOMA-IR in T2D patients, and improvements in HOMA-β positively correlate with baseline insulin resistance. These results demonstrate that tirzepatide’s therapeutic benefits are not only metabolic but also involve direct restoration of β-cell identity and function. This highlights β-cell reprogramming as a novel therapeutic avenue, thus supporting the broader clinical adoption of dual incretin receptor agonists.