GIP: the gut hormone that boosts insulin after eating (full-length form)
A natural gut hormone released after meals that tells the pancreas to make more insulin; this is the complete 42-unit version found in humans. Not a drug, a natural hormone studied in the lab.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
Named peptide fragment — synthesized for research; ClinicalTrials.gov trials registered for parent compound or class
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Endogenous peptide fragment — receptor binding/activity established in published literature; CT.gov evidence
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What this is
GIP (1–42) human is the full-length form of glucose-dependent insulinotropic polypeptide, a gut hormone released after a meal that tells the pancreas to secrete more insulin. It is one of the two main "incretin" hormones in humans, the other being GLP-1 (Seino et al., Journal of Diabetes Investigation, 2010). GIP is produced and released by K-cells in the upper small intestine in response to nutrients, and it acts on the GIP receptor (GIPR), a class B G-protein-coupled receptor on pancreatic β-cells. The stored sequence here is the 42-residue mature human peptide with an extra C-terminal cysteine appended (43 letters total), a tag commonly used to attach probes or surface coupling; the canonical bioactive human GIP(1–42) reported in the literature ends at Gln42 with the sequence YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (Bailey et al., Peptides, 2024).
History
GIP was originally characterised as a "gastric inhibitory polypeptide" — named for an inhibitory effect on gastric acid secretion — before its insulin-releasing activity led to the modern incretin framing and the renamed "glucose-dependent insulinotropic polypeptide" (Seino et al., 2010). Through the 2000s and 2010s, the field built out GIP's pharmacology in parallel with GLP-1, including the role of GIP in embryonic pancreatic development (Prasadan et al., Diabetes, 2011) and the development of tool antagonists such as (Pro3)GIP (Gault et al., Diabetologia, 2003; Sparre-Ulrich et al., British Journal of Pharmacology, 2015). The clinical relevance of GIP was substantially elevated by the success of tirzepatide, a dual GIP/GLP-1 receptor agonist (Willard et al., JCI Insight, 2020), and recent reviews now treat GIP and duodenal K-cells as a primary therapeutic target for obesity and type 2 diabetes in their own right (Bailey et al., Peptides, 2024; Müller et al., Molecular Metabolism, 2025).
What it does
After a meal, GIP is released from intestinal K-cells into the bloodstream and binds GIPR on pancreatic β-cells, where it amplifies glucose-stimulated insulin secretion — the defining "incretin effect" (Seino et al., 2010; Prasadan et al., 2011). Crucially, the insulin-releasing action is glucose-dependent, so GIP boosts insulin only when blood glucose is already rising. Beyond the pancreas, GIPR is expressed in adipose tissue, bone, and brain, and GIP signalling has been implicated in nutrient handling and energy balance, which is why duodenal GIP biology is now being explored as a therapeutic target for obesity and type 2 diabetes (Bailey et al., 2024; Müller et al., 2025). In rodent studies that combined the GIP antagonist (Pro3)GIP with the GLP-1 antagonist exendin(9–39), Gault and colleagues (2003) provided evidence that GIP — not GLP-1 — is the dominant physiological incretin in ob/ob mice, illustrating how large GIP's contribution to postprandial insulin release can be in vivo.
Evidence
- Human: Mechanistic and clinical literature on endogenous GIP biology in humans is reviewed in Seino et al. (2010), Bailey et al. (2024), and Müller et al. (2025). The most prominent therapeutic translation of GIP signalling in humans is via the dual GIP/GLP-1 agonist tirzepatide rather than native GIP itself; safety in that programme has been pooled meta-analytically (Zeng et al., Frontiers in Endocrinology, 2023).
- Animal: GIP-deficient and GIPR-pharmacology models show that GIP modulates glucose-induced insulin secretion and contributes to pancreatic β-cell development (Prasadan et al., 2011). Gault and colleagues (2003) used (Pro3)GIP and exendin(9–39) in ob/ob mice to dissect the relative contributions of GIP and GLP-1 to postprandial insulin release.
- In vitro: Sparre-Ulrich and colleagues (2015) showed that (Pro3)GIP is a full agonist at the human GIPR but only a partial agonist and competitive antagonist at the rat and mouse GIPR — a species-difference result that bears directly on how rodent GIP-blockade data should be interpreted for human drug design. Tirzepatide's signalling profile at the human GIPR (and GLP-1R) was characterised in receptor-occupancy and downstream-signalling assays by Willard and colleagues (2020), who described it as an "imbalanced and biased" dual agonist.
Known effects
- Amplification of glucose-stimulated insulin secretion — the canonical incretin effect; established human and animal physiology (Seino et al., 2010; Prasadan et al., 2011; Gault et al., 2003)
- Glucose-dependent pancreatic β-cell signalling via GIPR/cAMP — class B GPCR pharmacology (Seino et al., 2010; Graaf et al., Pharmacological Reviews, 2016)
- Role in obesity / type 2 diabetes therapeutics — GIPR is one of the two receptors engaged by the approved dual agonist tirzepatide (Willard et al., 2020; Bailey et al., 2024)
- Species-dependent pharmacology of GIPR ligands — (Pro3)GIP behaves very differently at human vs rodent receptors (Sparre-Ulrich et al., 2015)
Safety signals
Native GIP(1–42) is an endogenous hormone, not an approved therapeutic, so the relevant safety literature concerns drugs that engage the GIPR pharmacologically rather than the peptide itself. For the dual GIP/GLP-1 receptor agonist tirzepatide — the principal clinical readout for sustained GIPR agonism in humans — Zeng and colleagues (Frontiers in Endocrinology, 2023) conducted a systematic review and meta-analysis of randomised trials in type 2 diabetes and obesity to evaluate pancreatitis and gallbladder/biliary disease signals. Their meta-analysis is the primary safety reference in the dossier for clinical-grade GIPR engagement; no comparable adverse-event data exist for native GIP(1–42) administered as a drug, because that has not been a therapeutic strategy.
Regulatory status
- US/EU: GIP(1–42) human is the natural human hormone; it is not a marketed drug in its own right and does not carry an FDA or EMA approval as a therapeutic. Therapeutics that engage the GIP receptor in humans have advanced via dual incretin agonist programmes rather than native GIP (Willard et al., 2020; Bailey et al., 2024; Müller et al., 2025).
- Research reagent: Synthetic GIP(1–42) is widely used as a tool peptide for GIPR pharmacology in vitro and in vivo (Sparre-Ulrich et al., 2015; Gault et al., 2003).
Mechanism
GIP signals through GIPR, a class B (secretin-family) G-protein-coupled receptor (Seino et al., 2010; Graaf et al., 2016). Ligand binding activates Gαs, raising intracellular cAMP in the pancreatic β-cell; in the presence of elevated glucose, this potentiates insulin granule exocytosis — the molecular basis of the glucose-dependent incretin effect (Seino et al., 2010). The class B GPCR family that includes GIPR has been a productive target for peptide drug design (Graaf et al., 2016), and tirzepatide is the clearest example of using GIPR as part of a multireceptor strategy: Willard and colleagues (2020) characterised tirzepatide as an imbalanced, biased dual agonist at GIPR and GLP-1R, with non-equivalent occupancy and downstream signalling at the two receptors at clinically relevant exposures.
The stored sequence is YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQC. The bioactive human GIP(1–42) peptide that appears across the GIP literature ends at Gln42 (YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ, 42 residues; Bailey et al., 2024). The extra C-terminal cysteine in the stored sequence is not part of the natural mature peptide and is most consistent with a synthesis handle (for site-specific conjugation, surface immobilisation, or labelling) appended to the canonical 1–42 backbone; readers comparing this sequence to GIP(1–42) elsewhere should be aware of that single-residue extension.
Tool pharmacology around GIP includes the N-terminally substituted analog (Pro3)GIP, which is widely used in rodent studies as a GIPR antagonist but, as Sparre-Ulrich and colleagues (2015) showed, behaves as a full agonist at the human GIPR — a species mismatch that limits direct translation of rodent (Pro3)GIP data to human GIPR pharmacology. Combination antagonism with the GLP-1R antagonist exendin(9–39) has been used in vivo to apportion incretin contributions (Gault et al., 2003).
Open questions
- The therapeutic logic of GIPR engagement is still debated between agonism (as in tirzepatide; Willard et al., 2020) and antagonism (as motivated by parts of the (Pro3)GIP literature; Gault et al., 2003), and the dossier sources reflect both lines of inquiry without a settled resolution for human disease (Bailey et al., 2024; Müller et al., 2025).
- Species-specific differences at GIPR (Sparre-Ulrich et al., 2015) complicate extrapolation of rodent loss-of-function pharmacology to human drug design.
- Native GIP(1–42) has short circulating half-life as an unmodified peptide; long-acting GIPR-engaging molecules in humans have so far been multi-receptor analogs rather than stabilised native-sequence GIP (Willard et al., 2020; Müller et al., 2025).
- Roles of GIP and GIPR signalling outside the β-cell (adipose, bone, CNS) are flagged in recent reviews as active research areas (Bailey et al., 2024; Müller et al., 2025).
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does adding a cysteine at the very end of GIP change the strength or type of signal it sends through GIPR?
If true, labs using this common cysteine-tagged form might be measuring a weaker or altered GIP signal than they expect. Clarifying this would improve reproducibility in diabetes and obesity research, and help drug developers choose the right starting molecule.
Could scientists attach delivery or imaging tags to the cysteine on this GIP without destroying its activity?
If true, this common GIP variant could become a starting point for medicines that go specifically to the pancreas, brain, or fat tissue, making treatments more effective and reducing side effects.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8156806826591492 | boltz-2 |
| ranking score | 0.6226197481155396 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.496 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10771,
sequence = {YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQC},
target = {gipr},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}