Mahvash 病是一种罕见的常染色体隐性代谢性疾病，其特征是胰高血糖素受体基因 (GCGR) 的双等位基因功能丧失突变，可诱发显着的胰腺高胰高血糖素血症，导致 α 细胞增生和偶发的低血糖。利用 CRISPR-Cas9 技术，我们设计了一个小鼠模型，命名为 Gcgr V369M/V369M，在胰高血糖素受体 (GCGR) 中含有纯合 V369M 替换。尽管野生型 (WT) 和 Gcgr V369M/V369M 小鼠在外观或体重上没有表现出明显的差异，但大约 12 个月大的成年 Gcgr V369M/V369M 小鼠表现出空腹血糖水平显着降低，胆固醇水平升高和低密度脂蛋白胆固醇。此外，Gcgr V369M/V369M 小鼠中丙氨酸 (Ala)、脯氨酸 (Pro) 和精氨酸 (Arg) 等血浆氨基酸水平升高，导致 α 细胞增殖和高胰高血糖素血症。尽管 Gcgr V369M/V369M 小鼠存在持续的 α 细胞增生和循环胰高血糖素水平升高，但随着年龄的增长，两组之间的代谢差异逐渐缩小，伴随着 α 细胞增生的减少。在小鼠的整个生命周期（长达约 30 个月）中，胰腺神经内分泌肿瘤 (PNET) 并未出现。对 Gcgr V369M/V369M 小鼠代谢变化的长期观察为更深入地理解人类轻度 Mahvash 病提供了宝贵的见解。© 2024 作者。

Mahvash disease, a rare autosomal recessive metabolic disorder characterized by biallelic loss-of-function mutations in the glucagon receptor gene (GCGR), induces significant pancreatic hyperglucagonemia, resulting in α-cell hyperplasia and occasional hypoglycemia. Utilizing CRISPR-Cas9 technology, we engineered a mouse model, designated as Gcgr V369M/V369M, harboring a homozygous V369M substitution in the glucagon receptor (GCGR). Although wild-type (WT) and Gcgr V369M/V369M mice exhibited no discernible difference in appearance or weight, adult Gcgr V369M/V369M mice, approximately 12 months of age, displayed a notable decrease in fasting blood glucose levels and elevated the levels of cholesterol and low-density lipoprotein-cholesterol. Moreover, plasma amino acid levels such as alanine (Ala), proline (Pro) and arginine (Arg) were elevated in Gcgr V369M/V369M mice contributing to α-cell proliferation and hyperglucagonemia. Despite sustained α-cell hyperplasia and increased circulating glucagon levels in Gcgr V369M/V369M mice, metabolic disparities between the two groups gradually waned with age accompanied by a reduction in α-cell hyperplasia. Throughout the lifespan of the mice (up to approximately 30 months), pancreatic neuroendocrine tumors (PNETs) did not manifest. This prolonged observation of metabolic alterations in Gcgr V369M/V369M mice furnishes valuable insights for a deeper comprehension of mild Mahvash disease in humans.© 2024 The Authors.