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Michal Barabas Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust

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Isabel Huang-Doran Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Debbie Pitfield Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust

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Hazel Philips Department of Cardiology, Bedford Hospital NHS Trust, Bedford, UK

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Manoj Goonewardene Department of Cardiology, Bedford Hospital NHS Trust, Bedford, UK

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Ruth T Casey Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust

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Benjamin G Challis Wolfson Diabetes & Endocrine Clinic, Cambridge University Hospitals NHS Foundation Trust
IMED Biotech Unit, Clinical Discovery Unit, AstraZeneca, Cambridge, UK

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Summary

A 67-year-old woman presented with a generalised rash associated with weight loss and resting tachycardia. She had a recent diagnosis of diabetes mellitus. Biochemical evaluation revealed elevated levels of circulating glucagon and chromogranin B. Cross-sectional imaging demonstrated a pancreatic lesion and liver metastases, which were octreotide-avid. Biopsy of the liver lesion confirmed a diagnosis of well-differentiated grade 2 pancreatic neuroendocrine tumour, consistent with metastatic glucagonoma. Serial echocardiography commenced 4 years before this diagnosis demonstrated a progressive left ventricular dilatation and dysfunction in the absence of ischaemia, suggestive of glucagonoma-associated dilated cardiomyopathy. Given the severity of the cardiac impairment, surgical management was considered inappropriate and somatostatin analogue therapy was initiated, affecting clinical and biochemical improvement. Serial cross-sectional imaging demonstrated stable disease 2 years after diagnosis. Left ventricular dysfunction persisted, however, despite somatostatin analogue therapy and optimal medical management of cardiac failure. In contrast to previous reports, the case we describe demonstrates that chronic hyperglucagonaemia may lead to irreversible left ventricular compromise. Management of glucagonoma therefore requires careful and serial evaluation of cardiac status.

Learning points:

  • In rare cases, glucagonoma may present with cardiac failure as the dominant feature. Significant cardiac impairment may occur in the absence of other features of glucagonoma syndrome due to subclinical chronic hyperglucagonaemia.

  • A diagnosis of glucagonoma should be considered in patients with non-ischaemic cardiomyopathy, particularly those with other features of glucagonoma syndrome.

  • Cardiac impairment due to glucagonoma may not respond to somatostatin analogue therapy, even in the context of biochemical improvement.

  • All patients with a new diagnosis of glucagonoma should be assessed clinically for evidence of cardiac failure and, if present, a baseline transthoracic echocardiogram should be performed. In the presence of cardiac impairment these patients should be managed by an experienced cardiologist.

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Etienne Larger Department of Diabetology, Hôpital Bichat and University Paris Denis Diderot, Paris, France

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Nicolai J Wewer Albrechtsen Department of Biomedical Sciences
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Lars H Hansen Department of Molecular Signaling, Hagedorn Research Institute, Gentofte, Denmark

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Richard W Gelling Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

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Jacqueline Capeau Inserm UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
Sorbonne University, UPMC, University of Paris 6, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France

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Carolyn F Deacon Department of Biomedical Sciences
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Ole D Madsen Global Research External Affairs, Novo Nordisk A/S, 2760 Måløv, Denmark

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Fumiatsu Yakushiji Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
Department of Education Planning and Development, Faculty of Medicine, Toho University, Tokyo, Japan

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Pierre De Meyts Global Research External Affairs, Novo Nordisk A/S, 2760 Måløv, Denmark

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Jens J Holst Department of Biomedical Sciences
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Erica Nishimura Metabolic Disease Research, Novo Nordisk A/S, Måløv, Denmark

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Summary

Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3′ mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato–pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells.

Learning points:

  • Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.

  • Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.

  • A hepato–pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.

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Benjamin G Challis 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

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Nicolai J Wewer Albrechtsen 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

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Vishakha Bansiya Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Keith Burling Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Peter Barker Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Bolette Hartmann 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

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Fiona Gribble Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK

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Stephen O'Rahilly 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

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Jens J Holst 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

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Helen L Simpson Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK

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Summary

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.

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