Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery.

Tina Jorsal, Nicolai J Wewer Albrechtsen, Marie M Christensen, Brynjulf Mortensen, Erik Wandall, Ebbe Langholz, Steffen Friis, Dorte Worm, Cathrine Ørskov, René K Støving, Alin Andries, Claus B Juhl, Frederik Sørensen, Julie L Forman, Mechthilde Falkenhahn, Petra B Musholt, Stefan Theis, Philip J Larsen, Jens J Holst, Niels Vrang, Jacob Jelsing, Tina Vilsbøll, Filip K Knop

Journal: The Journal of clinical endocrinology and metabolism 2020;104(12):6403-6416

PMID: 31276156

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Abstract

CONTEXT

After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1).

OBJECTIVE

To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut.

DESIGN AND SETTING

Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark.

PARTICIPANTS

Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes.

INTERVENTIONS

Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB.

MAIN OUTCOME MEASURES

The 29-amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry-validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry.

RESULTS

Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon.

CONCLUSION

Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB.

Address: Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.; Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.; Endoscopic Unit, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.; Department of Medicine, Amager Hospital, University of Copenhagen, Copenhagen, Denmark.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Elite Research Center for Medical Endocrinology & Center for Eating Disorders, Odense University Hospital, Odense, Denmark.; Surgical Unit, Sydvestjysk Sygehus, Esbjerg, Denmark.; Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.; Sanofi Aventis, Frankfurt, Germany.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Gubra, Hørsholm, Denmark.; Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

DOI: 10.1210/jc.2019-00062

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MeSH Terms: Adolescent, Adult, Balloon Enteroscopy, Biomarkers, Blood Glucose, Case-Control Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Gastric Bypass, Gastric Inhibitory Polypeptide, Glucagon, Glucagon-Like Peptide 1, Glycated Hemoglobin, Humans, Insulin, Intestines, Male, Meals, Middle Aged, Obesity, Morbid, Postprandial Period, Prognosis, Prospective Studies, Young Adult