Wolfram Syndrome 1 (WS1) is a rare genetic disorder caused by WFS1 variants that disrupt Wolframin, an endoplasmic reticulum-associated protein essential for cellular stress responses, Ca2+ homeostasis, and autophagy. Here, we investigated how the c.316-1G>A and c.757A>T WFS1 mutations, which yield partially functional Wolframin, affect the molecular functions of β cells and explored the therapeutic potential of the Glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide. Pancreatic β cells obtained from patient-derived induced Pluripotent Stem Cells (iPSCs) carrying this WFS1 variant exhibited reduced insulin processing and impaired secretory granule maturation, as evidenced by proinsulin accumulation and decreased prohormone convertase PC1/3. Moreover, they exhibited dysregulated Ca2+ fluxes due to altered transcription of Ca2+-related genes, including CACNA1D, and significantly reduced SNAP25 levels, leading to uncoordinated oscillations and poor glucose responsiveness. Affected cells also showed increased autophagic flux and heightened susceptibility to inflammatory cytokine-induced apoptosis. Notably, liraglutide treatment rescued these defects by normalizing Ca2+ handling, enhancing insulin processing and secretion, and reducing apoptosis, likely through modulation of the unfolded protein response. These findings underscore the importance of defining mutation-specific dysfunctions in WS1 and support targeting the GLP-1/GLP-1R axis as a therapeutic strategy.

© 2025 by the American Diabetes Association.

Wolfram 综合征 1 型（WS1）是一种罕见的遗传性疾病，由 WFS1 变异引起，这些变异破坏了内质网相关的蛋白质 Wolframin。Wolframin 对细胞应激反应、Ca2+ 平衡和自噬至关重要。在这里，我们研究了 c.316-1G>A 和 c.757A>T WFS1 突变对 β 细胞分子功能的影响，这些突变产生的 Wolframin 部分具有功能性，并且探索了胰高血糖素样肽 1 受体 (GLP-1R) 激动剂利拉鲁肽的治疗潜力。从携带这种 WFS1 突变的患者诱导多能干细胞（iPSCs）获得的胰腺 β 细胞表现出降低的胰岛素加工和受损的分泌颗粒成熟，表现为前胰岛素积累以及 PC1/3 转换酶水平下降。此外，它们还由于与 Ca2+ 相关基因 CACNA1D 的转录改变导致钙离子通量失调，并且 SNAP25 水平显著降低，导致不协调的振荡和较差的葡萄糖反应性。受影响的细胞还表现出增加的自噬流以及对炎症细胞因子诱导的凋亡敏感性增强。值得注意的是，利拉鲁肽治疗通过调节未折叠蛋白反应来恢复正常 Ca2+ 处理、提高胰岛素加工和分泌并减少凋亡，从而纠正了这些缺陷。这些发现强调了在 WS1 中定义突变特异性功能障碍的重要性，并支持靶向 GLP-1/GLP-1R 轴作为治疗策略。

© 2025 by the American Diabetes Association.