Abstract
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.