Absence of PNET formation and normal longevity in a mouse model of Mahvash disease.

Mahvash disease, a rare autosomal recessive metabolic disorder characterized by biallelic loss-of-function mutations in the glucagon receptor gene (), induces significant pancreatic hyperglucagonemia, resulting in α-cell hyperplasia and occasional hypoglycemia. Utilizing CRISPR-Cas9 technology, we engineered a mouse model, designated as , harboring a homozygous V369M substitution in the glucagon receptor (GCGR). Although wild-type (WT) and mice exhibited no discernible difference in appearance or weight, adult 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 mice contributing to α-cell proliferation and hyperglucagonemia. Despite sustained α-cell hyperplasia and increased circulating glucagon levels in 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 mice furnishes valuable insights for a deeper comprehension of mild Mahvash disease in humans.