Diagnosis and Treatment > Investigation > GLP-1
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Search for other papers by Etienne Larger in
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Sorbonne University, UPMC, University of Paris 6, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Education Planning and Development, Faculty of Medicine, Toho University, Tokyo, Japan
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Search for other papers by Jens J Holst in
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Search for other papers by Erica Nishimura in
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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:
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Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.
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Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.
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A hepato–pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.
Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK
Search for other papers by Benjamin G Challis in
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Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Search for other papers by Nicolai J Wewer Albrechtsen in
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Search for other papers by Peter Barker in
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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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Search for other papers by Fiona Gribble in
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Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK
Search for other papers by Stephen O'Rahilly in
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Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Search for other papers by Jens J Holst in
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Search for other papers by Helen L Simpson in
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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
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PGDPs exhibit a diverse range of biological activities including critical roles in glucose and amino acid metabolism, energy homeostasis and gastrointestinal physiology.
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The clinical manifestations of proglucagon-expressing tumours may exhibit marked phenotypic variation due to the biochemical heterogeneity of their secreted peptide repertoire.
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Specific and precise biochemical assessment of individuals with proglucagon-expressing tumours may provide opportunities for improved diagnosis and clinical management.
UCLH Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK
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UCLH Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK
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UCLH Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK
National Institute of Health Research, Biomedical Research Centre, University College London Hospitals, London, W1T 7DN, UK
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Clinical and Experimental Surgery Department, Medical Research Institute, University of Alexandria, Hadara, Alexandria, 21561, Egypt
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UCLH Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK
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UCLH Centre for Weight Loss, Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK
National Institute of Health Research, Biomedical Research Centre, University College London Hospitals, London, W1T 7DN, UK
Search for other papers by Rachel L Batterham in
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Summary
Sleeve gastrectomy (SG) is the second most commonly performed bariatric procedure worldwide. Altered circulating gut hormones have been suggested to contribute post-operatively to appetite suppression, decreased caloric intake and weight reduction. In the present study, we report a 22-year-old woman who underwent laparoscopic SG for obesity (BMI 46 kg/m2). Post-operatively, she reported marked appetite reduction, which resulted in excessive weight loss (1-year post-SG: BMI 22 kg/m2, weight loss 52%, >99th centile of 1-year percentage of weight loss from 453 SG patients). Gastrointestinal (GI) imaging, GI physiology/motility studies and endoscopy revealed no anatomical cause for her symptoms, and psychological assessments excluded an eating disorder. Despite nutritional supplements and anti-emetics, her weight loss continued (BMI 19 kg/m2), and she required nasogastric feeding. A random gut hormone assessment revealed high plasma peptide YY (PYY) levels. She underwent a 3 h meal study following an overnight fast to assess her subjective appetite and circulating gut hormone levels. Her fasted nausea scores were high, with low hunger, and these worsened with nutrient ingestion. Compared to ten other post-SG female patients, her fasted circulating PYY and nutrient-stimulated PYY and active glucagon-like peptide 1 (GLP1) levels were markedly elevated. Octreotide treatment was associated with suppressed circulating PYY and GLP1 levels, increased appetite, increased caloric intake and weight gain (BMI 22 kg/m2 after 6 months). The present case highlights the value of measuring gut hormones in patients following bariatric surgery who present with anorexia and excessive weight loss and suggests that octreotide treatment can produce symptomatic relief and weight regain in this setting.
Learning points
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Roux-en-Y gastric bypass and SG produce marked sustained weight reduction. However, there is a marked individual variability in this reduction, and post-operative weight loss follows a normal distribution with extremes of ‘good’ and ‘poor’ response.
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Profound anorexia and excessive weight loss post-SG may be associated with markedly elevated circulating fasted PYY and post-meal PYY and GLP1 levels.
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Octreotide treatment can produce symptomatic relief and weight regain for post-SG patients that have an extreme anorectic and weight loss response.
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The present case highlights the value of measuring circulating gut hormone levels in patients with post-operative anorexia and extreme weight loss.
