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.