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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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E S Scott Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia

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G R Fulcher Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
University of Sydney, Sydney, Australia

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R J Clifton-Bligh Department of Endocrinology, Royal North Shore Hospital, Sydney Australia
University of Sydney, Sydney, Australia
Cancer Genetics Laboratory, Hormones & Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia

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Pancreatogenic diabetes is characterised by recurrent severe hypoglycaemia due to changes in both endocrine and exocrine functions. There are no guidelines to manage these individuals. Herein, we describe the post-operative management of two people who developed pancreatogenic diabetes following total pancreatectomy for neuroendocrine malignancy. In both individuals, diabetes was managed using sensor-augmented predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII). We demonstrate the benefit of sensor-augmented CSII in averting hypoglycaemia whilst optimising glycaemic control. Expected rates of severe hypoglycaemia in individuals with pancreatogenic diabetes can be averted with the use of continuous glucose monitoring (CGM) technology, optimising quality of life and reducing the risk of diabetes-related complications.

Learning points:

  • There are no clear guidelines to manage people with pancreatogenic diabetes.

  • We describe the use of CGM with predictive low-glucose suspend continuous subcutaneous insulin infusion (CSII) in the management of two individuals post-pancreatectomy.

  • Predictive low-glucose suspend technology can achieve excellent glycaemic control whilst avoiding recurrent and severe hypoglycaemia in people with pancreatogenic diabetes.

  • Predictive low-glucose suspend CGM should be considered as an effective therapeutic option for the management of pancreatogenic diabetes.

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Yasutaka Takeda Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Yukihiro Fujita Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Kentaro Sakai Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Tomoe Abe Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Tomonobu Nakamura Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Tsuyoshi Yanagimachi Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Hidemitsu Sakagami Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Jun Honjo Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Atsuko Abiko Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Yuichi Makino Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Masakazu Haneda Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan

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Summary

MEN1-associated pancreatic neuroendocrine tumors (pNETs) may potentially express distinct hormones, but the mechanism has not been elucidated. Transcription factors such as MafA and Pdx1 have been identified to lead to beta cell differentiation, while Arx and Brn4 to alpha cell differentiation in developing pancreas. We hypothesized those transcription factors are important to produce specific hormones in pNETs, similarly to developing pancreas, and examined the expression of transcription factors in a case of MEN1 who showed immunohistological coexistence of several hormone-producing pNETs including insulinoma. A 70-year-old woman was found to manifest hypoglycemia with non-suppressed insulinemia and hypercalcemia with elevated PTH level. She was diagnosed as MEN1 based on the manifestation of primary hyperparathyroidism, pituitary adenoma and insulinoma, with genetic variation of MEN1 gene. She had pylorus-preserving pancreaticoduodenectomy because CT scan and SACI test indicated that insulinoma was localized in the head of the pancreas. Histopathological finding was MEN1-associated NET, G1. Interestingly, immunohistological examination of the resected pancreas revealed that two insulinomas, a glucagon-positive NET and a multiple hormone-positive NET coexisted. Hence, we examined the expression of transcription factors immunohistochemically to elucidate the role of the transcription factors in MEN1-associated hormone-producing pNETs. We observed homogeneous expressions of MafA and Pdx1 in insulinomas and Arx in glucagon-positive NET, respectively. Moreover, multiple hormone-positive NETs expressed several transcription factors heterogeneously. Collectively, our results suggested that transcription factors could play important roles in the production of specific hormones in MEN1-associated pNETs, similar to islet differentiation.

Learning points:

  • To date, it has been shown that different hormone-producing tumors coexist in MEN1-associated pNETs; however, the underlying mechanism of the hormone production in MEN1-associated pNETs has not been well elucidated.

  • Although this case presented symptomatic hypoglycemia, several hormone-producing pNETs other than insulinoma also coexisted in the pancreas.

  • Immunohistochemical analysis showed MafA and Pdx1 expressions distinctly in insulinoma, and Arx expression particularly in a glucagon-positive NET, while a multiple hormone-positive NET expressed MafA, Pdx1 and Arx.

  • Collectively, clinicians should consider that several hormone-producing pNETs may coexist in a MEN1 case and examine both endocrinological and histopathological analysis of pNETs, regardless of whether symptoms related to the excess of hormones are observed or not.

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Gordon Sloan Department of Diabetes and Endocrinology, Sheffield Teaching Hospital, Sheffield, UK

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Amjad Ali Department of Diabetes and Endocrinology, Sheffield Teaching Hospital, Sheffield, UK

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Jonathan Webster Department of Diabetes and Endocrinology, Sheffield Teaching Hospital, Sheffield, UK

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Summary

Ketoacidosis occurring during lactation has been described infrequently. The condition is incompletely understood, but it appears to be associated with a combination of increased metabolic demands during lactation, reduction in carbohydrate intake and acute illness. We present a case of a 27-year-old woman, 8 weeks post-partum, who was exclusively breastfeeding her child whilst following a low carbohydrate diet. She developed gastroenteritis and was unable to tolerate an oral diet for several days. She presented with severe metabolic acidosis on admission with a blood 3-hydroxybutyrate of 5.4 mmol/L. She was treated with intravenous dextrose and intravenous sodium bicarbonate, and given dietary advice to increase her carbohydrate intake. She made a rapid and full recovery. We provide a summary of the common causes of ketoacidosis and compare our case with other presentations of lactation ketoacidosis.

Learning points:

  • Ketoacidosis in the lactating woman is a rare cause of raised anion gap metabolic acidosis.

  • Low carbohydrate intake, starvation, intercurrent illness or a combination of these factors could put breastfeeding women at risk of ketoacidosis.

  • Ketoacidosis in the lactating woman has been shown to resolve rapidly with sufficient carbohydrate intake and intravenous dextrose.

  • Early diagnosis and prompt treatment are essential because the condition is reported to be reversible with a low chance of recurrence with appropriate dietary advice.

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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.

Open access
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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Marta Guimarães
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Pedro Rodrigues
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Sofia S Pereira Clinical and Experimental Endocrinology, Department of Anatomy, Multidisciplinary Unit for Biomedical Research (UMIB), Instituto de Ciências Biomédicas Abel Salazar, University of Porto (ICBAS/UP), Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

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Mário Nora
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Gil Gonçalves
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Nicolai Wewer Albrechtsen NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Bolette Hartmann NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Jens Juul Holst NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Mariana P Monteiro Clinical and Experimental Endocrinology, Department of Anatomy, Multidisciplinary Unit for Biomedical Research (UMIB), Instituto de Ciências Biomédicas Abel Salazar, University of Porto (ICBAS/UP), Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
Endocrine Unit, Centro Hospitalar de Entre o Douro e Vouga, Rua Doutor Cândido Pinho, 4520-211, Santa Maria da Feira, Portugal

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Summary

Post-prandial hypoglycemia is frequently found after bariatric surgery. Although rare, pancreatic neuroendocrine tumors (pNET), which occasionally are mixed hormone secreting, can lead to atypical clinical manifestations, including reactive hypoglycemia. Two years after gastric bypass surgery for the treatment of severe obesity, a 54-year-old female with previous type 2 diabetes, developed post-prandial sweating, fainting and hypoglycemic episodes, which eventually led to the finding by ultrasound of a 1.8-cm solid mass in the pancreatic head. The 72-h fast test and the plasma chromogranin A levels were normal but octreotide scintigraphy showed a single focus of abnormal radiotracer uptake at the site of the nodule. There were no other clinical signs of hormone secreting pNET and gastrointestinal hormone measurements were not performed. The patient underwent surgical enucleation with complete remission of the hypoglycemic episodes. Histopathology revealed a well-differentiated neuroendocrine carcinoma with low-grade malignancy with positive chromogranin A and glucagon immunostaining. An extract of the resected tumor contained a high concentration of glucagon (26.707 pmol/g tissue), in addition to traces of GLP1 (471 pmol/g), insulin (139 pmol/g) and somatostatin (23 pmol/g). This is the first report of a GLP1 and glucagon co-secreting pNET presenting as hypoglycemia after gastric bypass surgery. Although pNET are rare, they should be considered in the differential diagnosis of the clinical approach to the post-bariatric surgery hypoglycemia patient.

Learning points

  • pNETs can be multihormonal-secreting, leading to atypical clinical manifestations.

  • Reactive hypoglycemic episodes are frequent after gastric bypass.

  • pNETs should be considered in the differential diagnosis of hypoglycemia after bariatric surgery.

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Kun Zhang Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Lukas J Lehner Department of Nephrology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Damaris Praeger Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Gert Baumann Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Fabian Knebel Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Marcus Quinkler Department of Endocrinology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Torsten K Roepke Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10115 Berlin, Germany

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Summary

Neuroendocrine tumours (NETs) represent a broad spectrum of tumours, of which the serotonin-producing carcinoid is the most common and has been shown to cause right ventricular heart failure. However, an association between heart failure and NETs other than carcinoid has not been established so far. In this case report, we describe a 51-year-old patient with a glucagon-producing NET of the pancreas who developed acute heart failure and even cardiogenic shock despite therapy. Heart failure eventually regressed after initialising i.v. treatment with the somatostatin analogue octreotide. Chromogranin A as a tumour marker was shown to be significantly elevated, and it decreased with clinical improvement of the patient. The effects of long-time stimulation of glucagon on the myocardium have not been studied yet; however, sarcoplasmic reticulum calcium leak can be discussed as a possible mechanism for glucagon-induced heart failure.

Learning points

  • Glucagonoma can be a cause for heart failure.

  • i.v. infusion of octreotide can be successfully used to treat glucagonoma-induced acute heart failure.

  • We suggest that cardiac function should be monitored in all NET patients.

Open access