Endoplasmic reticulum stress and forkhead box protein O1 inhibition mediate palmitic acid and high glucose-induced β-cell dedifferentiation.

BACKGROUND

Type 2 diabetes mellitus is characterized by pancreatic β-cell dysfunction and insulin resistance. Studies have suggested that β-cell dedifferentiation is one of the pathogeneses of β-cell dysfunction, but the detailed mechanism is still unclear. Most studies of β-cell dedifferentiation rely on rodent models and human pathological specimens. The development of systems can facilitate the exploration of β-cell dedifferentiation.

AIM

To investigate the molecular mechanism of β-cell dedifferentiation. Hence, an model of β-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1 832/13 cell line.

METHODS

The study was further analyzed using RNA-sequencing, transmission electron microscopy, quantitative real-time polymerase chain reaction and Western blot.

RESULTS

Results showed that the treatment of palmitic acid and high glucose significantly up-regulated β-cell forbidden genes and endocrine precursor cell marker genes, and down-regulated the expression of β-cell specific markers. Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum (ER) stress-related genes. Moreover, the results also showed that forkhead box O1 (Foxo1) inhibition potentiated genetic changes in β-cell dedifferentiation induced by palmitic acid and high glucose.

CONCLUSION

ER stress is sufficient to trigger β-cell dedifferentiation and is necessary for palmitic acid and high glucose-induced β-cell dedifferentiation. Foxo1 inhibition can further enhance these phenomena.