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

Abstract

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 α-cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which α-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 α-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 α-cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased α-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.

Pseudo-hemorrhagic region formation in pancreatic neuroendocrine tumors is a result of blood vessel dilation followed by endothelial cell detachment

“…Regarding the clinical significance of pseudo-hemorrhage, no statistically significant association was identified with tumor subtype, presence of metastasis, disease recurrence, patient sex or age of onset. In previous studies with genetically modified mice, including a RIP-TAG2 insulinoma model ( 21 ) and aprohormone convertase 2-knockout glucagonoma model ( 22 ), similar hemorrhagic regions resembling blood lakes have also been reported. This suggests that this type of hemorrhagic region may be a prominent feature of islet tumors.…”

Elusive liver factor that causes pancreatic α cell hyperplasia: A review of literature

“…While upregulated α cell neogenesis is also seen in the PC -/-mice throughout their lifespan, higher α cell proliferation is found at 3 mo [27] . The hyperplastic α cells in the Gcgr -/-mice exhibit abnormal differentiation.…”

“…Three other murine models also mimic the Mahvash disease in some aspects. The prohormone convertase 2 knockout (PC -/-) mice cannot make mature glucagon; they exhibit ACH and eventually develop PNETs [26,27] . The preproglucagon knockout (Gcg -/-) mice cannot make any proglucagonderived peptide hormones, including mature glucagon; they also exhibit ACH and eventually develop PNETs [28,29] .…”

“…Most α cells express embryonic α cell markers such as GLUT2 [32] . Abnormal α cell differentiation is also seen in humans with mutated Gcgr and in the PC -/-mice as they both express glucagon-like peptide 1, which is normally not expressed in the α cells [21,27] .…”

Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population

“…In mice, complete knockout of the prohormone convertase PC2 in the C57Bl/6j strain results in hypoglycemia due to the total absence of glucagon [8, 9]; PC2 knockout in the 129Sv background results in even larger hypoglycemic effects [10]. These mouse studies indicate that unlike other processing enzyme mutations, loss of PC2 activity may be associated with protection from diabetes and obesity rather than with susceptibility [8, 11, 12]. …”