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.
GLP-1-comparable insulin releaseLEAP2₃₈₋₄₇ 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
What the researchers 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.
Why it 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 numbers in context
LEAP2 upregulated post-RYGB; LEAP238-47 insulinotropic comparable to GLP-1; 10 subjects infused; no glucoregulatory effect at chosen dose
How the study worked
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.
Who was studied
20 obese subjects before/after RYGB + 10 healthy volunteers for infusion
What this study cannot 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).
How to read the evidence
Moderate evidence: combines human genomic, in vitro, and clinical infusion data. In vivo negative result at one dose limits conclusions about therapeutic potential.
When this study was published
Published 2021. LEAP2 research has continued to expand as a metabolic regulatory peptide.
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.
Questions still open
- 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?
Common questions
Why does gastric bypass cure diabetes so quickly?
What is LEAP2?
Read the original research
Identification and Metabolic Profiling of a Novel Human Gut-derived LEAP2 Fragment.
The Journal of clinical endocrinology and metabolism, 106(2), e966-e981
Citation
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