Identification of a human gut-derived LEAP2 fragment as a novel insulin secretagogue

The mechanisms underlying Roux-en-Y gastric bypass (RYGB) surgery-induced weight loss and the immediate postoperative beneficial metabolic effects associated with the operation remain uncertain. We aimed to identify novel gut-derived peptides with therapeutic potential in obesity and/or diabetes by determining genome-wide expression patterns in isolated human small intestinal enteroendocrine cells (EECs) obtained from 20 obese subjects undergoing RYGB and again three months later by upper enteroscopy. RYGB increased expression levels of the inverse ghrelin receptor agonist, liver-enriched antimicrobial peptide 2 (LEAP2), and a secreted endogenous LEAP2 fragment (LEAP238-47) demonstrated insulinotropic properties in vitro, promoting an increase in insulin release comparable to the gut hormone glucagon-like peptide 1. LEAP238-47 showed reciprocal effects on growth hormone secretagogue receptor (GHSR) activity, suggesting that the insulinotropic action of the peptide may be directly linked to attenuation of tonic GHSR activity. The fragment was infused to healthy human individuals, but compared to placebo, no glucoregulatory effect was observed in the chosen dose. In conclusion, small intestinal LEAP2 expression was upregulated after RYGB; and the fragment LEAP238-47 showed a strong in vitro insulinotropic effect, but failed to elicit glucoregulatory effects when infused in healthy human subjects. Overall design: Global transcriptome profiling of gut segments from patients undergoing RYGB surgery.