The ghrelin-GHSR-LEAP2 system plays dual roles in type 2 diabetes pathology and protection
Ghrelin promotes hyperglycemia by suppressing insulin and inducing resistance, while its antagonist LEAP2 enhances insulin secretion—yet ghrelin also protects against diabetic complications through anti-inflammatory and antioxidant mechanisms.
Quick Facts
What This Study Found
Ghrelin activates GHSR1a to suppress insulin, induce resistance, and promote hepatic glucose output (worsening diabetes), while LEAP2 antagonizes these effects. Paradoxically, ghrelin also protects against diabetic complications via anti-inflammatory, antioxidant, and anti-apoptotic pathways.
Key Numbers
No specific clinical data; reviews molecular mechanisms of ghrelin, GHSR, and LEAP2 in T2DM pathophysiology.
How They Did This
Narrative review of molecular mechanisms and physiological functions of the ghrelin-GHSR-LEAP2 system in type 2 diabetes.
Why This Research Matters
Understanding ghrelin's dual role—both harmful (promoting hyperglycemia) and protective (preventing complications)—is essential for designing therapies that block the bad effects while preserving the beneficial ones.
The Bigger Picture
The ghrelin-LEAP2 axis represents a natural regulatory system that could be therapeutically exploited alongside GLP-1 drugs. LEAP2-based therapies might complement GLP-1 agonists by addressing additional aspects of glucose dysregulation.
What This Study Doesn't Tell Us
Narrative review. Many mechanistic insights from preclinical models. Clinical translation of ghrelin-axis modulation for diabetes is still early-stage.
Questions This Raises
- ?Can LEAP2-based therapies improve glycemic control without losing ghrelin's protective effects?
- ?How does the ghrelin system interact with GLP-1 agonist therapy in diabetes?
- ?Could selective GHSR1a modulators separate the harmful and beneficial effects of ghrelin?
Trust & Context
- Key Stat:
- Dual role paradox Ghrelin worsens blood sugar but protects against diabetic complications, while its natural antagonist LEAP2 improves insulin secretion
- Evidence Grade:
- Narrative review synthesizing preclinical and clinical evidence. Good mechanistic overview but limited clinical translation data.
- Study Age:
- Published in 2025; covers current understanding of ghrelin-LEAP2 in diabetes.
- Original Title:
- Ghrelin-GHSR-LEAP2 system in the pathophysiology of type 2 diabetes.
- Published In:
- iScience, 28(10), 113573 (2025)
- Authors:
- Pu, Yueli, Yang, Jianmei, Li, Wei(4), Wen, Yi, Zheng, Chunmei, Li, Yonglin, Wu, Lijuan, Ming, Yao, Zhao, Changying, Chen, Chen
- Database ID:
- RPEP-13121
Evidence Hierarchy
Summarizes existing research without a strict systematic method.
What do these levels mean? →Frequently Asked Questions
What is LEAP2 and how does it relate to diabetes?
LEAP2 (liver-expressed antimicrobial peptide 2) is a natural antagonist of the ghrelin receptor. It blocks ghrelin's blood sugar-raising effects and enhances insulin secretion. Higher LEAP2 levels are associated with better glucose control, making it a potential therapeutic target for type 2 diabetes.
Why can't we just block ghrelin to treat diabetes?
Because ghrelin has a paradoxical dual role: while it raises blood sugar (harmful in diabetes), it also protects against diabetic complications through anti-inflammatory effects. Simply blocking all ghrelin signaling could worsen complications even while improving glucose control.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-13121APA
Pu, Yueli; Yang, Jianmei; Li, Wei; Wen, Yi; Zheng, Chunmei; Li, Yonglin; Wu, Lijuan; Ming, Yao; Zhao, Changying; Chen, Chen. (2025). Ghrelin-GHSR-LEAP2 system in the pathophysiology of type 2 diabetes.. iScience, 28(10), 113573. https://doi.org/10.1016/j.isci.2025.113573
MLA
Pu, Yueli, et al. "Ghrelin-GHSR-LEAP2 system in the pathophysiology of type 2 diabetes.." iScience, 2025. https://doi.org/10.1016/j.isci.2025.113573
RethinkPeptides
RethinkPeptides Research Database. "Ghrelin-GHSR-LEAP2 system in the pathophysiology of type 2 d..." RPEP-13121. Retrieved from https://rethinkpeptides.com/research/pu-2025-ghrelinghsrleap2-system-in-the
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.