Reference SummaryYu R, Endocrinol Nutr 2012 Nov;59(9):523-30

Title

Glucagon receptor is required for long-term survival: a natural history study of the Mahvash disease in a murine model.

Authors

Yu R; Ren SG; Mirocha J

Journal

Endocrinol Nutr

Volume

59

Issue

9

Year

2012

Pages

523-30

Abstract

BACKGROUND AND AIM: We 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 METHOD: Wild 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. RESULTS: The 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. CONCLUSION: The 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.

Links

22951296 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
DBA/1LacJ Adrenal gland tumor Adrenal gland

0

DBA/1LacJ-Gcgrtm1Jcp/+ Adrenal gland tumor Adrenal gland

0.79

DBA/1LacJ-Gcgrtm1Jcp Adrenal gland tumor Adrenal gland

0

CE/WyDi Pancreas - Islet of Langerhans - Alpha cell glucagonoma Pancreas - Islet of Langerhans - Alpha cell

observed

DBA/1LacJ Pancreas - Islet of Langerhans dysplasia Pancreas - Islet of Langerhans

0

DBA/1LacJ-Gcgrtm1Jcp/+ Pancreas - Islet of Langerhans dysplasia Pancreas - Islet of Langerhans

0

DBA/1LacJ-Gcgrtm1Jcp Pancreas - Islet of Langerhans dysplasia Pancreas - Islet of Langerhans

observed

DBA/1LacJ-Gcgrtm1Jcp Pancreas adenoma Pancreas

observed

CE/WyDi Pancreas insulinoma Pancreas

observed

DBA/1LacJ Pancreas lesion Pancreas

0

DBA/1LacJ-Gcgrtm1Jcp/+ Pancreas lesion Pancreas

0

DBA/1LacJ-Gcgrtm1Jcp Pancreas lesion Pancreas

30.36

DBA/1LacJ-Gcgrtm1Jcp Pancreas tumor Pancreas

observed - 100

DBA/1LacJ Pancreas tumor Pancreas

0

DBA/1LacJ-Gcgrtm1Jcp/+ Pancreas tumor Pancreas

0

DBA/1LacJ-Gcgrtm1Jcp Pancreas tumor - endocrine Pancreas

10

DBA/1LacJ Pancreas tumor - endocrine Pancreas

0

DBA/1LacJ-Gcgrtm1Jcp/+ Pancreas tumor - endocrine Pancreas

0 - observed

CE/WyDi Pancreas tumor - mixed Pancreas

observed

DBA/1LacJ Pancreas tumor - neuroendocrine Pancreas

0

DBA/1LacJ-Gcgrtm1Jcp/+ Pancreas tumor - neuroendocrine Pancreas

0

DBA/1LacJ-Gcgrtm1Jcp Pancreas tumor - neuroendocrine Pancreas

30.36

DBA/1LacJ Pelvis tumor Pelvis

1.92

DBA/1LacJ-Gcgrtm1Jcp/+ Pelvis tumor Pelvis

1.57

DBA/1LacJ-Gcgrtm1Jcp Pelvis tumor Pelvis

0

DBA/1LacJ (Unspecified organ) lesion - benign (Unspecified organ)

0 - observed

DBA/1LacJ-Gcgrtm1Jcp/+ (Unspecified organ) lesion - benign (Unspecified organ)

0 - observed

DBA/1LacJ-Gcgrtm1Jcp (Unspecified organ) lesion - benign (Unspecified organ)

0 - observed

DBA/1LacJ (Unspecified organ) tumor (Unspecified organ)

1.92

DBA/1LacJ-Gcgrtm1Jcp/+ (Unspecified organ) tumor (Unspecified organ)

2.36

DBA/1LacJ-Gcgrtm1Jcp (Unspecified organ) tumor (Unspecified organ)

30.36