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.

Learning points: 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.

Figure 1

Photographs of case 1 showing (A) necrolytic migratory erythema before treatment with octreotide (100 μg thrice daily) and progressive resolution following 4 days (B) and 21 days (C) of octreotide therapy.

Figure 2

(A) Computed tomography of the abdomen demonstrating thickened small bowl. (B) Somatostatin receptor scintigraphy demonstrating multiple hepatic metastases. Immunohistochemical analysis of a biopsied liver metastasis showing positive staining for (C) glucagon and negative staining for (D) insulin.

Figure 3

(A) Illustrates measured levels of proglucagon-derived peptides from case 1: glucagon, glicentin, oxyntomodulin, amidated total GLP-1, intact GLP-1, glycine-extended GLP-1 and GLP-2. Hormone levels appear as: before (after) somatostatin analogue therapy in pM. Red arrows illustrate C- or N-terminal, or side-viewing antibodies used for measurement. ‘?’ Refers to N-terminal elongated glucagon. (B) Gel filtration profile of plasma from case 1. The left y-axis reflects hormone levels of collected fractions (100, herewith 38–70 is illustrated) using C-terminal glucagon assay (black curve), C-terminal amidated GLP-1 assay (red curve) and N-terminal GLP-2 assay (green curve). Calibrators (stippled black line) include ¹²⁵I albumin and ²²Na. GLI refers to glucagon-like immunoreactivity.

Figure 4

(A) Illustrates measured levels of different proglucagon-derived peptides from case 2: glucagon, glicentin, oxyntomodulin, amidated total GLP-1, intact GLP-1, glycine-extended GLP-1 and GLP-2. Hormone levels appear as: before (after) somatostatin analogue therapy in pM. Red arrows illustrate C- or N-terminal, or side-viewing antibodies used for measurement. (B) Gel filtration profile of plasma from case 2. The left y-axis reflects hormone levels of collected fractions (100, hereof 38–70 is illustrated) using C-terminal glucagon assay (black curve), C-terminal amidated GLP-1 assay (red curve) and N-terminal GLP-2 assay (green curve). Calibrators (stippled black line) include ¹²⁵I albumin and ²²Na. ‘?’ Refers to a probable biologically inactive GLP-2 immunoreactive peptide moiety.