Faraj Noura, Hoogaars Willem M H, Duinkerken B H Peter, Wolters Anouk H G, Kats Kim, Dekkers Mette C, Zaldumbide Arnaud, Giepmans Ben N G
Department of Biomedical Sciences, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
Diabetologia. 2025 Apr 28. doi: 10.1007/s00125-025-06432-4.
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.
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.
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.
目的/假设：β细胞内质网（ER）应激过度会损害其增殖，并导致自身免疫反应，如1型糖尿病中β细胞的破坏。外分泌腺与β细胞的相互作用会影响β细胞的生长和功能。值得注意的是，在不同类型的糖尿病中，外分泌腺异常经常与β细胞负荷过重同时出现，这表明外分泌腺应激可能会诱导β细胞内质网应激和β细胞丢失。虽然外分泌腺应激与β细胞功能之间的因果关系无法在人体中得到证实，但可以在斑马鱼模型中进行研究。受精后120小时，斑马鱼幼虫发育出具有类似人类形态的胰腺，为研究胰腺相互作用提供了一个有价值的动态模型。我们的目标是使用转基因斑马鱼模型和报告基因特异性地靶向外分泌腺细胞，并研究β细胞的状态。
为了探究外分泌腺损伤对β细胞健康的影响，我们利用硝呋吡醇-硝基还原酶系统构建了一种新型斑马鱼模型，可实现外分泌胰腺的消融。随后，我们通过实时监测动态细胞事件，如内质网应激、细胞凋亡以及β细胞数量和体积的变化，评估了其对β细胞的体内影响。
斑马鱼的外分泌腺损伤使胰腺体积减少了约50%，并改变了其形态。由此产生的外分泌腺损伤在60%-90%的β细胞中诱导了内质网应激，并导致β细胞数量减少了约50%。
结论/解读：斑马鱼模型为研究外分泌腺细胞与β细胞之间的相互作用提供了一个强大的平台，从而有助于进一步深入了解驱动1型糖尿病等胰腺疾病的机制。
