Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation
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) agon...
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000018 |
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| author | Iona Davies Alice E. Adriaenssens William R. Scott David Carling Kevin G. Murphy James S. Minnion Stephen R. Bloom Ben Jones Tricia M-M. Tan |
| author_facet | Iona Davies Alice E. Adriaenssens William R. Scott David Carling Kevin G. Murphy James S. Minnion Stephen R. Bloom Ben Jones Tricia M-M. Tan |
| author_sort | Iona Davies |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-beae0242efdd426385ed133f64a119f3 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-beae0242efdd426385ed133f64a119f32025-02-01T04:11:58ZengElsevierMolecular Metabolism2212-87782025-02-0192102094Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisationIona Davies0Alice E. Adriaenssens1William R. Scott2David Carling3Kevin G. Murphy4James S. Minnion5Stephen R. Bloom6Ben Jones7Tricia M-M. Tan8Section of Endocrinology and Investigative Medicine, Imperial College London, United KingdomDepartment of Neuroscience, Physiology, and Pharmacology, University College London, London, United KingdomMRC Laboratory of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, W12 0NN, United KingdomMRC Laboratory of Medical Sciences, London, United KingdomSection of Endocrinology and Investigative Medicine, Imperial College London, United KingdomSection of Endocrinology and Investigative Medicine, Imperial College London, United KingdomSection of Endocrinology and Investigative Medicine, Imperial College London, United KingdomSection of Endocrinology and Investigative Medicine, Imperial College London, United Kingdom; Corresponding author.Section of Endocrinology and Investigative Medicine, Imperial College London, United Kingdom; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2212877825000018Glucose-dependent insulinotropic polypeptide receptor (GIPR)Receptor desensitisationβ-arrestinReceptor internalisationObesityType 2 diabetes |
| spellingShingle | Iona Davies Alice E. Adriaenssens William R. Scott David Carling Kevin G. Murphy James S. Minnion Stephen R. Bloom Ben Jones Tricia M-M. Tan Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation Molecular Metabolism Glucose-dependent insulinotropic polypeptide receptor (GIPR) Receptor desensitisation β-arrestin Receptor internalisation Obesity Type 2 diabetes |
| title | Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation |
| title_full | Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation |
| title_fullStr | Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation |
| title_full_unstemmed | Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation |
| title_short | Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation |
| title_sort | chronic gipr agonism results in pancreatic islet gipr functional desensitisation |
| topic | Glucose-dependent insulinotropic polypeptide receptor (GIPR) Receptor desensitisation β-arrestin Receptor internalisation Obesity Type 2 diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000018 |
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