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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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