Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery.
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McGavigan, Anne K
Biggs, Emma K
Hornigold, David C
Hardwick, Richard H
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Larraufie, P., Roberts, G. P., McGavigan, A. K., Kay, R., Li, J., Leiter, A., Melvin, A., et al. (2019). Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery.. Cell reports, 26 (6), 1399-1408.e6. https://doi.org/10.1016/j.celrep.2019.01.047
Bariatric surgery is widely used to treat obesity, and additionally improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide-YY (PYY) and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains hotly debated. Here we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1R) post-gastrectomy in lean humans using Exendin-9, or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery, but instead we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut, and is a key driver of enhanced insulin secretion.
Intestinal Mucosa, Animals, Mice, Inbred C57BL, Humans, Mice, Obesity, Peptide YY, Glucose, Peptide Fragments, Hypoglycemic Agents, Postoperative Period, Homeostasis, Adult, Middle Aged, Female, Male, Enteroendocrine Cells, Bariatric Surgery, Glucagon-Like Peptide 1, Transcriptome, Insulin Secretion
RNA-sequencing was undertaken at the CRUK Cambridge Institute Genomics Core. Cell sorting was performed at the NIHR Cambridge BRC Cell Phenotyping Hub. PL received a Society for Endocrinology Early Career Grant. GR received an Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] and a Royal College of Surgeons Research Fellowship. The work was partially funded by a project grant from the EFSD/Novo Nordisk Programme for Diabetes Research in Europe.
Wellcome Trust (100574/Z/12/Z)
WELLCOME TRUST (106262/Z/14/Z & 106263/Z/14/Z)
European Foundation for the Study of Diabetes (EFSD) (unknown)
Royal College of Surgeons of England (unknown)
MEDICAL RESEARCH COUNCIL (MR/M009041/1)
MEDICAL RESEARCH COUNCIL (MR/M024873/1)
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External DOI: https://doi.org/10.1016/j.celrep.2019.01.047
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288928
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/