Hormonal
Chronic administration of GIP receptor agonists (specifically GIP108) causes functional desensitization of the GIP receptor in pancreatic islets, reducing the efficacy of subsequent glucose-lowering challenges.
Long-term use of GIP-based therapies (like tirzepatide) triggers a biological adaptation where the pancreas becomes less responsive to the drug's glucose-lowering signal. This is a known mechanism called desensitization. However, the drug still promotes weight loss, suggesting the benefit comes from multiple pathways, not just pancreatic sensitivity. If glycemic control wanes, dose adjustments may be necessary.
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.
Why this rating
High-quality in vivo and ex vivo mechanistic data using specific transgenic mouse models and long-acting agonists, though limited to murine models.
Source
Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation
Iona Davies et al. · Molecular Metabolism · 2025
DOI 10.1016/j.molmet.2025.102094
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