Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β‐cell function in NAFPD by inhibiting MST1‐Foxo3a signalling pathway.

GPR119 agonists are being developed to safeguard the function of pancreatic β‐cells, especially in the context of non‐alcoholic fatty pancreas disease (NAFPD) that is closely associated with β‐cell dysfunction. This study aims to employ a drug repurposing strategy to screen GPR119 agonists and explore their potential molecular mechanisms for enhancing β‐cell function in the context of NAFPD. MIN6 cells were stimulated with palmitic acid (PA), and a NAFPD model was established in GPR119−/− mice fed with a high‐fat diet (HFD). Terazosin, identified through screening, was utilized to assess its impact on enhancing β‐cell function via the MST1‐Foxo3a pathway and mitophagy. Terazosin selectively activated GPR119, leading to increased cAMP and ATP synthesis, consequently enhancing insulin secretion. Terazosin administration improved high blood glucose, obesity, and impaired pancreatic β‐cell function in NAFPD mice. It inhibited the upregulation of MST1‐Foxo3a expression in pancreatic tissue and enhanced damaged mitophagy clearance, restoring autophagic flux, and improving mitochondrial quantity and structure in β‐cells. Nevertheless, GPR119 deficiency negated the positive impact of terazosin on pancreatic β‐cell function in NAFPD mice and abolished its inhibitory effect on the MST1‐Foxo3a pathway. Terazosin activates GPR119 on the surface of pancreatic β‐cells, enhancing mitophagy and alleviating β‐cell dysfunction in the context of NAFPD by suppressing the MST1‐Foxo3a signalling pathway. Terazosin could be considered a priority treatment for patients with concomitant NAFPD and hypertension. [ABSTRACT FROM AUTHOR]