Binding kinetics, bias, receptor internalization and effects on insulin secretion in vitro and in vivo of a novel GLP-1R/GIPR dual agonist, HISHS-2001
Author(s)
Type
Journal Article
Abstract
Aims
The use of incretin analogues has emerged as an effective approach to achieve both enhanced insulin secretion and weight loss in Type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off-target effects remain a complication of using these agents, and modified versions with optimised pharmacological profiles and/or biased signalling are sought.
Materials and Methods
Ligand synthesis was achieved using standard solid-phase techniques. Assessments of GLP-1R-binding kinetics, G protein recruitment and receptor internalisation were performed using biochemical and imaging approaches. Insulin secretion was measured in purified mouse and human islets, and drug efficacy was assessed in hyperglycaemic db/db mice.
Results
We describe the synthesis and properties of a molecule which binds to both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R and GIPR) to enhance insulin secretion. HISHS-2001 shows increased affinity at the GLP-1R, as well as a tendency towards reduced internalisation and recycling at this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. HISHS-2001 also displayed significantly greater bias towards cAMP generation versus β-arrestin 2 recruitment compared to tirzepatide. In contrast, Gαs recruitment was lower versus tirzepatide at the GLP-1R, but unchanged at the GIPR. Administered to obese hyperglycaemic db/db mice, HISHS-2001 increased circulating insulin whilst lowering body weight and HbA1c with similar efficacy to tirzepatide at substantially lower doses.
Conclusion
HISHS-2001 represents a novel dual receptor agonist with a promising pharmacological profile and actions. Future clinical studies will be needed to assess the safety and efficacy of this molecule in humans.
The use of incretin analogues has emerged as an effective approach to achieve both enhanced insulin secretion and weight loss in Type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off-target effects remain a complication of using these agents, and modified versions with optimised pharmacological profiles and/or biased signalling are sought.
Materials and Methods
Ligand synthesis was achieved using standard solid-phase techniques. Assessments of GLP-1R-binding kinetics, G protein recruitment and receptor internalisation were performed using biochemical and imaging approaches. Insulin secretion was measured in purified mouse and human islets, and drug efficacy was assessed in hyperglycaemic db/db mice.
Results
We describe the synthesis and properties of a molecule which binds to both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R and GIPR) to enhance insulin secretion. HISHS-2001 shows increased affinity at the GLP-1R, as well as a tendency towards reduced internalisation and recycling at this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. HISHS-2001 also displayed significantly greater bias towards cAMP generation versus β-arrestin 2 recruitment compared to tirzepatide. In contrast, Gαs recruitment was lower versus tirzepatide at the GLP-1R, but unchanged at the GIPR. Administered to obese hyperglycaemic db/db mice, HISHS-2001 increased circulating insulin whilst lowering body weight and HbA1c with similar efficacy to tirzepatide at substantially lower doses.
Conclusion
HISHS-2001 represents a novel dual receptor agonist with a promising pharmacological profile and actions. Future clinical studies will be needed to assess the safety and efficacy of this molecule in humans.
Date Issued
2025-10-01
Date Acceptance
2025-07-18
Citation
Diabetes, Obesity and Metabolism, 2025, 27 (10), pp.5938-5949
ISSN
1462-8902
Publisher
Wiley
Start Page
5938
End Page
5949
Journal / Book Title
Diabetes, Obesity and Metabolism
Volume
27
Issue
10
Copyright Statement
© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40831316
Subjects
antidiabetic drug
antiobesity drug
beta cell function
BETA-CELLS
Endocrinology & Metabolism
GLP-1 analogue
GLUCAGON-LIKE PEPTIDE-1
insulin secretion
Life Sciences & Biomedicine
Science & Technology
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2025-08-20