| First Author | Jones HB | Year | 2014 |
| Journal | Int J Exp Pathol | Volume | 95 |
| Issue | 1 | Pages | 29-48 |
| PubMed ID | 24456331 | Mgi Jnum | J:236905 |
| Mgi Id | MGI:5810061 | Doi | 10.1111/iep.12066 |
| Citation | Jones HB, et al. (2014) Islets of Langerhans from prohormone convertase-2 knockout mice show alpha-cell hyperplasia and tumorigenesis with elevated alpha-cell neogenesis. Int J Exp Pathol 95(1):29-48 |
| abstractText | Antagonism of the effects of glucagon as an adjunct therapy with other glucose-lowering drugs in the chronic treatment of diabetes has been suggested to aggressively control blood glucose levels. Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with alpha-cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which alpha-cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. PC2-ko and wild-type (WT) mice were maintained drug-free, and cohorts of these groups sampled at 3, 12 and 18 months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. WT mice showed no islet tumours up to termination of the study, but PC2-ko animals displayed marked changes in islet morphology from alpha-cell hypertrophy/hyperplasia/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6-8 months. Islet hyperplasias and tumours primarily consisted of alpha-cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased alpha-cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the PC2-ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis. |
