Summary: Bariatric surgery is widely used to treat obesity and 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 debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) 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; 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. : Bariatric surgery is associated with enhanced postprandial gut hormone release, particularly of GLP-1, which increases insulin secretion and glucose clearance. Larraufie et al. show that higher gut hormone levels are due not to changes in enteroendocrine cell characteristics or tissue hormone content but to altered flow of nutrients that stimulates more distal enteroendocrine cells. Keywords: bariatric surgery, GLP-1, enteroendocrine cells, peptidomics, mass spectrometry, transcriptomics, intestinal transit, gut hormones
