Research
Hormonal
Tirzepatide stimulates glucagon secretion in human islets primarily through GIP receptor activation, which overrides the glucagon-suppressing effect of GLP-1 receptor activation.
Tirzepatide increases glucagon secretion via the GIP receptor, which might seem counterintuitive for a diabetes drug. However, this is a normal physiological response to nutrient sensing, and the drug's overall effect is still a significant reduction in blood glucose due to its powerful insulin-stimulating effects.
GoodSupportsHIGH confidence
antagonism of the GIPR, but not GLP-1R, completely blocked the ability of either hGIP or tirzepatide to stimulate glucagon secretion.
Why this rating
Consistent findings across multiple human donor islet sets.
Source
The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets
Kimberley El et al. · Nature Metabolism · 2023
DOI 10.1038/s42255-023-00811-0
mechanism_onlyCited 109×
Read the paper DOI resolved against Crossref · corpus check 2026-06-10
More from this paper
- Tirzepatide requires GIP receptor (GIPR) activation to stimulate insulin secretion in human islets, as blocking GIPR consistently reduces this response.Good
- Tirzepatide stimulates insulin secretion in mouse islets predominantly through the GLP-1 receptor, with minimal GIP receptor contribution at therapeutic doses.Good
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