Islets of Langerhans from prohormone convertase-2 knockout mice show α-cell hyperplasia and tumorigenesis with elevated α-cell neogenesis

Antagonism of the effects of glucagonas 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 glucagoneffects, by targeting glucagonsecretion or disabling the glucagon receptor, is associated with α-cell hyperplasia. We evaluated the influence of total glucagonwithdrawal on isletsof Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which α-cell hyperplasiais present from a young age and persists throughout life, in order to understand whether or not sustained glucagondeficit would lead to islettumorigenesis. 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 islettumours up to termination of the study, but PC2-ko animals displayed marked changes in isletmorphology from α-cell hypertrophy/ hyperplasia/ atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6–8 months. Islet hyperplasiasand tumours primarily consisted of α-cells associated to varying degrees with other isletendocrine cell types. In addition to substantial increases in isletneoplasia, increased α-cell neogenesisassociated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagonsignal results in tumorigenesis and that the PC2-ko mouse represents a valuable model for investigation of islettumours and pancreatic ductal neogenesis.