Tumor necrosis factor-α promotes abnormal glucose metabolism after acute pancreatitis by inducing islet β-cell apoptosis via Bax/Bcl-2/caspase-3 signaling pathway.

BACKGROUND: Tumor necrosis factor-α (TNF-α) has been implicated in the development of diabetes following chronic pancreatitis. However, its role in abnormal glucose metabolism (AGM) after acute pancreatitis (AP) and post-pancreatitis diabetes mellitus remains unclear. AIM: To investigate the role of TNF-α in AP-associated AGM and its effects on islet β-cell apoptosis, focusing on the underlying molecular mechanisms. METHODS: Clinical data were collected to assess AGM's incidence and identify the characteristics in 369 AP patients. In vitro, AP models were established using lipopolysaccharide in 266-6 acinar cells and MIN-6 β-cells. Cell proliferation, apoptosis, and protein expression were analyzed using the Cell Counting Kit-8 assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and western blotting. The TNF-α and insulin concentration in co-culture medium was measured by enzyme-linked immunosorbent assay. In vivo, an AP mouse model was induced using sodium taurocholate, and pancreatic tissues were analyzed through hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and western blotting. TNF-α levels were assessed by enzyme-linked immunosorbent assay. A TNF-α inhibitor was applied to the AP cell model to reassess apoptosis and protein expression. RESULTS: AGM occurred in 40.38% of AP patients. Body mass index, severity grade, recurrence frequency, and lung injury were significantly associated with AGM. AP models in 266-6 and MIN-6 cells showed reduced β-cell proliferation, insulin secretion, and increased apoptosis, which correlated with inflammation severity. Similar findings of β-cell apoptosis were confirmed in the mouse model. TNF-α levels were significantly elevated in AP models, with higher levels in severe inflammation. Increased Bax and caspase-3 expression and decreased Bcl-2 expression were observed in both in vitro and in vivo models. These changes intensified with increasing inflammation. TNF-α inhibition reduced apoptosis and altered protein expression patterns, decreasing Bax and caspase-3, while increasing Bcl-2 in MIN-6 cells. CONCLUSION: TNF-α contributes to β-cell apoptosis and AGM in AP through the Bax/Bcl-2/caspase-3 signaling pathway, suggesting TNF-α as a potential therapeutic target for preventing AP-associated AGM.