The ghrelin-GHSR-LEAP2 system plays dual roles in type 2 diabetes pathology and protection | Research

The takeaway

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.

Dual role paradox
Ghrelin worsens blood sugar but protects against diabetic complications, while its natural antagonist LEAP2 improves insulin secretion

What the researchers 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.

Why it 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 numbers in context

No specific clinical data; reviews molecular mechanisms of ghrelin, GHSR, and LEAP2 in T2DM pathophysiology.

How the study worked

Narrative review of molecular mechanisms and physiological functions of the ghrelin-GHSR-LEAP2 system in type 2 diabetes.

Who was studied

N/A (reviews preclinical and clinical literature on T2DM)

What this study cannot tell us

Narrative review. Many mechanistic insights from preclinical models. Clinical translation of ghrelin-axis modulation for diabetes is still early-stage.

How to read the evidence

Narrative review synthesizing preclinical and clinical evidence. Good mechanistic overview but limited clinical translation data.

When this study was published

Published in 2025; covers current understanding of ghrelin-LEAP2 in diabetes.

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.

Questions still open

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?

Common 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.

Read the original research

Ghrelin-GHSR-LEAP2 system in the pathophysiology of type 2 diabetes.

iScience, 28(10), 113573

View on PubMed ↗Publisher’s paper ↗

Citation

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