<b>Liraglutide treatment reverses unconventional cellular defects in induced pluripotent stem cell-derived β cells harboring a partially functional </b><b><i>WFS1</i></b><b> variant</b>

<p dir="ltr">Wolfram Syndrome 1 (WS1) is a rare genetic disorder caused by <i>WFS1</i> 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 <i>WFS1</i> 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 <i>WFS1 </i>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 <i>CACNA1D</i>, and significantly reduced <i>SNAP25</i> 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.</p>