title: Heterogeneity of glucagonomas due to differential processing of proglucagon-derived peptides.
abstract: Pancreatic neuroendocrine tumours (pNETs) secreting proglucagon are associated with phenotypic heterogeneity. Here, we describe two patients with pNETs and varied clinical phenotypes due to differential processing and secretion of proglucagon-derived peptides (PGDPs). Case 1, a 57-year-old woman presented with necrolytic migratory erythema, anorexia, constipation and hyperinsulinaemic hypoglycaemia. She was found to have a grade 1 pNET, small bowel mucosal thickening and hyperglucagonaemia. Somatostatin analogue (SSA) therapy improved appetite, abolished hypoglycaemia and improved the rash. Case 2, a 48-year-old male presented with diabetes mellitus, diarrhoea, weight loss, nausea, vomiting and perineal rash due to a grade 1 metastatic pNET and hyperglucagonaemia. In both cases, plasma levels of all measured PGDPs were elevated and attenuated following SSA therapy. In case 1, there was increased production of intact glucagon-like peptide 1 (GLP-1) and GLP-2, similar to that of the enteroendocrine L cell. In case 2, pancreatic glucagon was elevated due to a pancreatic α-cell-like proglucagon processing profile. In summary, we describe two patients with pNETs and heterogeneous clinical phenotypes due to differential processing and secretion of PGDPs. This is the first description of a patient with symptomatic hyperinsulinaemic hypoglycaemia and marked gastrointestinal dysfunction due to, in part, a proglucagon-expressing pNET.
  
  
  CONCLUSIONS
  PGDPs exhibit a diverse range of biological activities including critical roles in glucose and amino acid metabolism, energy homeostasis and gastrointestinal physiology.The clinical manifestations of proglucagon-expressing tumours may exhibit marked phenotypic variation due to the biochemical heterogeneity of their secreted peptide repertoire.Specific and precise biochemical assessment of individuals with proglucagon-expressing tumours may provide opportunities for improved diagnosis and clinical management.
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK ; Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Challis
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark ; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark.
authors.forename: Nicolai J Wewer
authors.initials: NJ
authors.lastname: Albrechtsen
authors.affiliation: Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK.
authors.forename: Vishakha
authors.initials: V
authors.lastname: Bansiya
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Burling
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Barker
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark ; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark.
authors.forename: Bolette
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gribble
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK ; Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark ; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Simpson