Pancreatic exocrine damage induces beta cell stress in zebrafish larvae

Aims/hypothesis

Excessive endoplasmic reticulum (ER) stress in beta cells can impair proliferation and contribute to autoimmune responses such as the destruction of beta cells in type 1 diabetes. Exocrine–beta cell interactions affect beta cell growth and function. Notably, exocrine abnormalities are frequently observed alongside overloaded beta cells in different types of diabetes, suggesting that exocrine stress may induce beta cell ER stress and loss. While a cause–consequence relationship between exocrine stress and beta cell function cannot be addressed in humans, it can be studied in a zebrafish model. Larvae develop a pancreas with a human-like morphology by 120 h post-fertilisation, providing a valuable dynamic model for studying pancreatic interactions. Our aim was to target exocrine cells specifically and address beta cell status using transgenic zebrafish models and reporters.

Methods

To explore the impact of exocrine damage on beta cell fitness, we generated a novel zebrafish model allowing exocrine pancreas ablation, using a nifurpirinol–nitroreductase system. We subsequently assessed the in vivo effects on beta cells by live-monitoring dynamic cellular events, such as ER stress, apoptosis and changes in beta cell number and volume.

Results

Exocrine damage in zebrafish decreased pancreas volume by approximately 50% and changed its morphology. The resulting exocrine damage induced ER stress in 60–90% of beta cells and resulted in a ~50% reduction in their number.

Conclusions/interpretation

The zebrafish model provides a robust platform for investigating the interplay between exocrine cells and beta cells, thereby enhancing further insights into the mechanisms driving pancreatic diseases such as type 1 diabetes.

Graphical Abstract