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

The dual incretin receptor agonist tirzepatide improves {beta}-cell function in T2D patients, but the underlying mechanism remains unclear. This study aimed to elucidate the molecular pathway through which tirzepatide restores {beta}-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 {beta}-cell mass, proliferation, or apoptosis. Instead, tirzepatide reversed {beta}-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-{beta}, and decreased HOMA-IR. Improvement in HOMA-{beta} correlated positively with baseline insulin resistance. Hence, our study suggested that tirzepatide restores {beta}-cell function in T2D by reprogramming stressed {beta} cells and re-establishing {beta}-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 HIGHLIGHTSO_LITirzepatide restores {beta} cell identity and function without altering {beta} cell mass in HFD induced diabetic mice. C_LIO_LITirzepatide reverses {beta}-cell dedifferentiation and restores key {beta}-cell transcription factors (PDX1, MAFA) through reactivation of the AKT-FOXO1 signaling pathway. C_LIO_LITirzepatide increases HOMA-{beta} and decreases HOMA-IR in T2D patients, and improvements in HOMA-{beta} positively correlate with baseline insulin resistance. C_LIO_LIThese results demonstrate that tirzepatides therapeutic benefits are not only metabolic but also involve direct restoration of {beta}-cell identity and function. This highlights {beta}-cell reprogramming as a novel therapeutic avenue, thus supporting the broader clinical adoption of dual incretin receptor agonists. C_LI