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Endocrine Abstracts (2015) 38 P152 | DOI: 10.1530/endoabs.38.P152

SFEBES2015 Poster Presentations Neoplasia, cancer and late effects (31 abstracts)

Phenotypic heterogeneity associated with proglucagon-expressing tumours is due to differential processing and secretion of proglucagon-derived peptides

Ben Challis 1 , Nicolai Albrechtsen 2 , Vishakha Bansiya 1 , Keith Burling 1 , Peter Barker 1 , Bolette Hartmann 2 , Fiona Gribble 1 , Stephen O’Rahilly 1 , Jens Holst 2 & Helen Simpson 1


1University of Cambridge Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK; 2Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.


Context: Pancreatic neuroendocrine tumours (NETs) overexpressing glucagon are associated with phenotypic heterogeneity. Objective: To correlate clinical phenotype with detailed analysis of plasma levels of proglucagon-derived peptides (PGDPs) in subjects with proglucagon-expressing tumours using specific immunoassays and gel filtration profiles to elaborate molecular heterogeneity of PGDPs, before and after somatostatin analogues.

Case 1: A 57 year old women presented with necrolytic migratory erythema, refractory constipation, anorexia and hyperinsulinaemic hypoglycaemia. Liver biopsy demonstrated a grade 1 NET. CT revealed a pancreatic lesion with liver metastases and profound small bowel mucosal thickening. Biochemical investigations revealed hyperproglucagonaemia (3504 pmol/l). Octreotide treatment increased appetite, abolished hypoglycaemia and rapidly improved her rash.

Case 2: A 48 year old male presented with newly diagnosed diabetes mellitus, weight loss, vomiting and perineal rash. CT revealed a pancreatic lesion with widespread hepatic and bony metastases. Biopsy demonstrated a grade 1 NET. Biochemical investigations revealed hyperproglucagonaemia (786 pmol/l) and somatostatin analogues were commenced. Results: In both cases, plasma levels of detectable proglucagon, glucagon, GLP-1 and GLP-2 were elevated compared with healthy subjects, and attenuated by somatostatin analogues. In case 1, proglucagon processing by the tumour was similar to that of the intestinal L cell with increased production of intact GLP-1 and GLP-2 and manifesting clinically with hyperinsulinaemic hypoglycaemia and thickened small bowel, respectively. Unlike healthy controls, fifty percent of GLP-1 was glycine extended. In case 2, the tumour secreted a pancreatic α-cell profile of PGDPs and diabetes was the consequence of elevated intact glucagon. Case 2 had higher detectable levels of GLP-2-like immunoreactivity, however gel filtation profiling revealed the predominance of a lower molecular weight peptide with biological inactivity.

Conclusion: Differential processing of PGDPs by proglucagon-secreting pNETs explains the clinical heterogeneity associated with these tumours. Moreover, detailed phenotyping of such patients may provide improved understanding of PGDP biology in man.

Volume 38

Society for Endocrinology BES 2015

Edinburgh, UK
02 Nov 2015 - 04 Nov 2015

Society for Endocrinology 

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