Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic β cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1’s interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.

Wolfram 综合征是一种罕见的多系统疾病，其特征是儿童期糖尿病和进行性神经变性。大多数病例归因于单个基因的致病变异，Wolfram 综合征 1 ( WFS1）。目前没有针对 Wolfram 综合征的疾病改善疗法，因为 WFS1 缺失的分子后果仍然难以捉摸。因为糖尿病是 Wolfram 综合征的第一个诊断症状，我们旨在进一步检查 WFS1 在高血糖背景下胰腺 β 细胞中的功能。WFS1 在大鼠胰岛素瘤 (INS1) 细胞中的敲除 (KO) 会损害钙稳态和蛋白激酶 B/Akt 信号传导，并随后降低细胞活力和葡萄糖刺激的胰岛素分泌。通过重新表达 WFS1、过表达 WFS1 的相互作用伙伴神经元钙传感器-1 (NCS1) 或用钙蛋白酶抑制剂和异丁司特治疗来靶向钙稳态，逆转了 WFS1-KO 细胞中观察到的缺陷。总的来说，