Glucagon receptor is required for long-term survival: A natural history study of the Mahvash disease in a murine model |
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| Authors: | Run Yu Song-Guang Ren James Mirocha |
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| Institution: | 1. Division of Endocrinology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA;2. Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA;3. Research Institute and General Clinical Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA;1. Clermont Université, Université d’Auvergne, EA7280, Laboratoire de Neuropsychopharmacologie des systèmes dopaminergiques sous corticaux, Clermont-Ferrand, France;2. CHU Clermont-Ferrand, Service de Neurologie, 63000 Clermont-Ferrand, France;1. Division of Radiobiology and Molecular Environmental Research, University of Tuebingen, Germany;2. Department of Radiation Oncology, University of Tuebingen, Germany;1. Institute of Veterinary Virology (current name: Institute of Virology and Immunology), Vetsuisse Faculty University of Bern, Laenggass-Str. 122, CH-3001 Bern, Switzerland;2. Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland;1. Department of Molecular and Cellular Biology;2. Division of Hematopoietic Stem Cell and Leukemia Research;3. Department of Virology;4. Division of Comparative Medicine, Beckman Research Institute, City of Hope, Duarte, CA;5. Regulus Therapeutics, San Diego, CA;1. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, People''s Republic of China;2. Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States |
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| Abstract: | Background and aimWe have described a novel Mahvash disease of hyperglucagonemia and pancreatic neuroendocrine tumors (PNETs) associated with an inactivating glucagon receptor mutation, and identified the glucagon receptor-deficient (Gcgr?/?) mice as its murine model. We aim to elucidate the natural history of the rare Mahvash disease by long-term observation of the Gcgr?/? mice.Materials and methodWild type (WT) (n = 52), heterozygous (n = 127), and Gcgr?/? (n = 56) mice living under standard vivarium conditions were observed without specific treatments over 22 months. Autopsy was performed on dead animals.ResultsThe WT and heterozygous mice did not exhibit any measurable differences. The Gcgr?/? mice became progressively lethargic and cachexic after 12 months. Random glucose levels were stable in WT and heterozygous mice but decreased with age in the Gcgr?/? mice. At the end of observation, 28/56 Gcgr?/?, 7/52 WT, and 24/127 heterozygous mice died. The survival curve of Gcgr?/? mice began to separate from those of WT and heterozygous mice at 12 months and the survival difference widened with age. At 18 months, survival probability was 17% for Gcgr?/? mice but 77% for WT and 81% for heterozygous mice. Autopsy revealed numerous PNETs up to 15 mm in diameter in most well-preserved Gcgr?/? pancreata (17/20) but none in WT or heterozygous ones. Four Gcgr?/? mice developed liver or subcutaneous metastasis.ConclusionThe untreated Mahvash disease may cause cachexia, severe hypoglycemia, and early death. Patients with Mahvash disease need to undergo life-long surveillance for PNETs. Functional glucagon receptor is thus required for long-term survival. |
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