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.