Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Objectives
There is renewed interest in targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) for treatment of obesity and type 2 diabetes. G-protein coupled receptor desensitisation is suggested to reduce the long-term efficacy of glucagon-like-peptide 1 receptor (GLP-1R) agonists and may similarly affect the efficacy of GIPR agonists. We explored the extent of pancreatic GIPR functional desensitisation with sustained agonist exposure.
Methods
A long-acting GIPR agonist, GIP108, was used to probe the effect of sustained agonist exposure on cAMP responses in dispersed pancreatic islets using live cell imaging, with rechallenge cAMP responses after prior agonist treatment used to quantify functional desensitisation. Receptor internalisation and β-arrestin-2 activation were investigated in vitro using imaging-based assays. Pancreatic mouse GIPR desensitisation was assessed in vivo via intraperitoneal glucose tolerance testing.
Results
GIP108 treatment led to weight loss and improved glucose homeostasis in mice. Prolonged exposure to GIPR agonists produced homologous functional GIPR desensitisation in isolated islets. GIP108 pre-treatment in vivo also reduced the subsequent anti-hyperglycaemic response to GIP re-challenge. GIPR showed minimal agonist-induced internalisation or β-arrestin-2 activation.
Conclusions
Although GIP108 chronic treatment improved glucose tolerance, it also resulted in partial desensitisation of the pancreatic islet GIPR. This suggests that ligands with reduced desensitisation tendency might lead to improved in vivo efficacy. Understanding whether pancreatic GIPR desensitisation affects the long-term benefits of GIPR agonists in humans is vital to design effective metabolic pharmacotherapies.
There is renewed interest in targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) for treatment of obesity and type 2 diabetes. G-protein coupled receptor desensitisation is suggested to reduce the long-term efficacy of glucagon-like-peptide 1 receptor (GLP-1R) agonists and may similarly affect the efficacy of GIPR agonists. We explored the extent of pancreatic GIPR functional desensitisation with sustained agonist exposure.
Methods
A long-acting GIPR agonist, GIP108, was used to probe the effect of sustained agonist exposure on cAMP responses in dispersed pancreatic islets using live cell imaging, with rechallenge cAMP responses after prior agonist treatment used to quantify functional desensitisation. Receptor internalisation and β-arrestin-2 activation were investigated in vitro using imaging-based assays. Pancreatic mouse GIPR desensitisation was assessed in vivo via intraperitoneal glucose tolerance testing.
Results
GIP108 treatment led to weight loss and improved glucose homeostasis in mice. Prolonged exposure to GIPR agonists produced homologous functional GIPR desensitisation in isolated islets. GIP108 pre-treatment in vivo also reduced the subsequent anti-hyperglycaemic response to GIP re-challenge. GIPR showed minimal agonist-induced internalisation or β-arrestin-2 activation.
Conclusions
Although GIP108 chronic treatment improved glucose tolerance, it also resulted in partial desensitisation of the pancreatic islet GIPR. This suggests that ligands with reduced desensitisation tendency might lead to improved in vivo efficacy. Understanding whether pancreatic GIPR desensitisation affects the long-term benefits of GIPR agonists in humans is vital to design effective metabolic pharmacotherapies.
Date Issued
2025-02-01
Date Acceptance
2025-01-03
Citation
Molecular Metabolism, 2025, 92
ISSN
2212-8778
Publisher
Elsevier BV
Journal / Book Title
Molecular Metabolism
Volume
92
Copyright Statement
© 2025 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39788289
PII: S2212-8778(25)00001-8
Subjects
Glucose-dependent insulinotropic polypeptide receptor (GIPR)
Obesity
Receptor desensitisation
Receptor internalisation
Type 2 diabetes
β-arrestin
Animals
Mice
Receptors, Gastrointestinal Hormone
Islets of Langerhans
Male
Gastric Inhibitory Polypeptide
Mice, Inbred C57BL
beta-Arrestin 2
Humans
Diabetes Mellitus, Type 2
Glucose Tolerance Test
Cyclic AMP
Publication Status
Published
Coverage Spatial
Germany
Article Number
102094
Date Publish Online
2025-01-07