Gastric Bypass Increases LEAP2 Peptide That Stimulates Insulin Release
RYGB surgery upregulates LEAP2 expression, and a circulating LEAP2 fragment (LEAP2₃₈₋₄₇) stimulated insulin release from human islets comparable to GLP-1, though it failed to show glucoregulatory effects when infused in healthy humans.
Quick Facts
What This Study Found
RYGB upregulated LEAP2 expression. LEAP2₃₈₋₄₇ demonstrated robust insulinotropic activity comparable to GLP-1 in human islets, likely via GHSR attenuation. But IV infusion in 10 healthy humans at the chosen dose showed no glucoregulatory effect.
Key Numbers
LEAP2 upregulated post-RYGB; LEAP238-47 insulinotropic comparable to GLP-1; 10 subjects infused; no glucoregulatory effect at chosen dose
How They Did This
Genome-wide expression in isolated human intestinal enteroendocrine cells from 20 obese subjects pre/post-RYGB. LEAP2₃₈₋₄₇ tested for insulin secretion in human islets and GHSR activity. Phase 1 infusion study in 10 healthy volunteers.
Why This Research Matters
Understanding how RYGB improves diabetes could lead to non-surgical treatments. LEAP2 is a novel metabolic peptide that could be developed as a new diabetes drug, though the dose and patient population need optimization.
The Bigger Picture
LEAP2 is emerging as a key metabolic peptide beyond its role as a ghrelin antagonist. Its upregulation after bariatric surgery connects gut anatomy changes to hormonal mechanisms, potentially explaining RYGB's diabetes benefits and opening new therapeutic avenues.
What This Study Doesn't Tell Us
Healthy volunteer infusion study — diabetic patients might respond differently. Dose may have been too low. In vitro insulinotropic activity didn't translate in vivo at the tested dose. Small clinical sample (n=10).
Questions This Raises
- ?Would higher LEAP2 fragment doses or longer infusions show glucoregulatory effects?
- ?Does LEAP2 fragment show activity in diabetic patients with insulin resistance?
- ?Could LEAP2 be combined with GLP-1 agonists for enhanced metabolic effects?
Trust & Context
- Key Stat:
- GLP-1-comparable insulin release LEAP2₃₈₋₄₇ stimulated insulin secretion from human islets at levels comparable to GLP-1 — but this didn't translate in vivo at the tested dose in healthy subjects
- Evidence Grade:
- Moderate evidence: combines human genomic, in vitro, and clinical infusion data. In vivo negative result at one dose limits conclusions about therapeutic potential.
- Study Age:
- Published 2021. LEAP2 research has continued to expand as a metabolic regulatory peptide.
- Original Title:
- Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment.
- Published In:
- The Journal of clinical endocrinology and metabolism, 106(2), e966-e981 (2021)
- Authors:
- Hagemann, Christoffer A, Zhang, Chen, Hansen, Henrik H(2), Jorsal, Tina, Rigbolt, Kristoffer T G, Madsen, Martin R, Bergmann, Natasha C, Heimbürger, Sebastian M N, Falkenhahn, Mechthilde, Theis, Stefan, Breitschopf, Kristin, Holm, Stephanie, Hedegaard, Morten A, Christensen, Mikkel B, Vilsbøll, Tina, Holst, Birgitte, Vrang, Niels, Jelsing, Jacob, Knop, Filip K
- Database ID:
- RPEP-05433
Evidence Hierarchy
Frequently Asked Questions
Why does gastric bypass cure diabetes so quickly?
This study suggests that RYGB changes how gut cells produce hormones, increasing LEAP2 which can stimulate insulin release. Combined with changes in GLP-1 and other gut hormones, these hormonal shifts may explain the rapid diabetes improvement seen within days of surgery.
What is LEAP2?
LEAP2 (liver-expressed antimicrobial peptide 2) was originally identified as an antimicrobial peptide but is now recognized as a key metabolic regulator. It blocks the ghrelin receptor and, based on this study, may also directly stimulate insulin release.
Read More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-05433APA
Hagemann, Christoffer A; Zhang, Chen; Hansen, Henrik H; Jorsal, Tina; Rigbolt, Kristoffer T G; Madsen, Martin R; Bergmann, Natasha C; Heimbürger, Sebastian M N; Falkenhahn, Mechthilde; Theis, Stefan; Breitschopf, Kristin; Holm, Stephanie; Hedegaard, Morten A; Christensen, Mikkel B; Vilsbøll, Tina; Holst, Birgitte; Vrang, Niels; Jelsing, Jacob; Knop, Filip K. (2021). Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment.. The Journal of clinical endocrinology and metabolism, 106(2), e966-e981. https://doi.org/10.1210/clinem/dgaa803
MLA
Hagemann, Christoffer A, et al. "Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment.." The Journal of clinical endocrinology and metabolism, 2021. https://doi.org/10.1210/clinem/dgaa803
RethinkPeptides
RethinkPeptides Research Database. "Identification and Metabolic Profiling of a Novel Human Gut-..." RPEP-05433. Retrieved from https://rethinkpeptides.com/research/hagemann-2021-identification-and-metabolic-profiling
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.