Absence of PNET formation and normal longevity in a mouse model of Mahvash disease
Yingna Xu,
Qiaofeng Liu,
Chuan-Wei Chen,
Qiuying Wang,
Tianyuan Du,
Run Yu,
Qingtong Zhou,
Dehua Yang,
Ming-Wei Wang
Affiliations
Yingna Xu
Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
Qiaofeng Liu
School of Pharmacy, Fudan University, Shanghai, 201203, China
Chuan-Wei Chen
Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China
Qiuying Wang
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
Tianyuan Du
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
Run Yu
Division of Endocrinology, Diabetes, and Metabolism, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
Qingtong Zhou
Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China
Dehua Yang
Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Corresponding author. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Ming-Wei Wang
Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China; Department of Chemistry, School of Science, The University of Tokyo, Tokyo, 113-0033, Japan; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, 570228, China; Corresponding author. Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China.
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 GcgrV369M/V369M, harboring a homozygous V369M substitution in the glucagon receptor (GCGR). Although wild-type (WT) and GcgrV369M/V369M mice exhibited no discernible difference in appearance or weight, adult GcgrV369M/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 GcgrV369M/V369M mice contributing to α-cell proliferation and hyperglucagonemia. Despite sustained α-cell hyperplasia and increased circulating glucagon levels in GcgrV369M/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 GcgrV369M/V369M mice furnishes valuable insights for a deeper comprehension of mild Mahvash disease in humans.
