GIP (Glucose-dependent Insulinotropic Polypeptide)

The native 42-amino-acid incretin hormone secreted by intestinal K cells after meals, which potentiates glucose-stimulated insulin release and whose receptor is a target shared by tirzepatide and retatrutide; no GIP drug product exists.

Also referenced as: Gastric inhibitory polypeptide, GIP(1-42), GIP 1-42

Also appears in: Weight loss

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What is GIP (Glucose-dependent Insulinotropic Polypeptide)?

GIP is a native human gut hormone, a single-chain peptide of 42 amino acids released by enteroendocrine K cells of the duodenum and upper jejunum within minutes of a meal, most strongly in response to absorbed fat and carbohydrate. It was isolated from porcine intestine by Brown and colleagues on the basis of its ability to inhibit gastric acid secretion, which gave it its original name, gastric inhibitory polypeptide; the full sequence was published in 1971 (Brown and Dryburgh, Canadian Journal of Biochemistry, 1971;49(8):867–872). Two years later the same molecule was shown to stimulate insulin release in humans when glucose was raised at the same time (Dupre et al., Journal of Clinical Endocrinology and Metabolism, 1973;37(5):826–828), and the name was later re-read as glucose-dependent insulinotropic polypeptide. Human GIP is cleaved from a 153-residue precursor, preproGIP (Takeda et al., Proceedings of the National Academy of Sciences, 1987;84(20):7005–7008). Together with GLP-1 it accounts for the incretin effect, the larger insulin response to oral glucose than to an intravenous glucose infusion matched for the same blood glucose curve (Nauck et al., Journal of Clinical Endocrinology and Metabolism, 1986;63(2):492–498).

No pharmaceutical product contains GIP itself. Its importance to current medicine is indirect: the GIP receptor is one of the two targets of tirzepatide, one of the three targets of retatrutide, and the target blocked by the antibody component of maridebart cafraglutide. Synthetic human GIP(1-42) is available on the research-peptide market for laboratory use, and GMP-grade GIP is infused in investigator-led physiology studies.

How it works

• Glucose-dependent potentiation of insulin secretion. GIP binds a class B G-protein-coupled receptor on pancreatic beta cells, cloned in 1993 and also found in gut, adipose tissue, heart, adrenal cortex and brain (Usdin et al., Endocrinology, 1993;133(6):2861–2870). Receptor activation raises cAMP and amplifies glucose-triggered insulin release; at normal or low glucose the insulinotropic action is small or absent. Under a hyperglycemic clamp in ten healthy men, physiological GIP more than doubled the insulin secretion rate (Christensen et al., Diabetes, 2011;60(12):3103–3109).
• A bifunctional effect on glucagon. The same study showed that during euglycemia and insulin-induced hypoglycemia GIP raised glucagon rather than insulin, while during hyperglycemia it left glucagon suppression unchanged, so GIP behaves as a glucose-dependent stabilizer acting on both islet hormones (Christensen et al., Diabetes, 2011;60(12):3103–3109). Cell-specific receptor knockouts in mice confirmed that GIP’s contribution to glucose tolerance runs through both alpha cells and beta cells (El et al., Science Advances, 2021;7(11):eabf1948).
• Rapid inactivation by DPP-4. Dipeptidyl peptidase-4 removes the two N-terminal residues to produce GIP(3-42), which is not insulinotropic. After intravenous infusion, intact GIP(1-42) accounted for only about 37% of total GIP immunoreactivity in healthy subjects, and the plasma half-life of the intact peptide was 7.3 minutes in healthy subjects and 5.2 minutes in people with type 2 diabetes (Deacon et al., Journal of Clinical Endocrinology and Metabolism, 2000;85(10):3575–3581). This is why every therapeutic program built on the GIP receptor uses a stabilized analog or an antibody rather than the native hormone.
• Extra-pancreatic actions on fat, bone and brain. In lean volunteers, GIP appeared to enhance fatty acid re-esterification in abdominal adipose tissue (Asmar et al., Diabetes, 2010;59(9):2160–2163). In C-peptide-negative people with type 1 diabetes, GIP suppressed the bone-resorption marker CTX by up to 59% versus 24% with saline at low glycemia and 59% versus 7% at high glycemia, an anti-resorptive action independent of insulin (Christensen et al., Journal of Clinical Endocrinology and Metabolism, 2018;103(1):288–294). In mice, central nervous system GIP receptors are required for the weight-lowering effect of acylated GIP and for the added benefit of GLP-1/GIP co-agonism over GLP-1 alone, and activating hypothalamic GIP-receptor cells suppresses food intake (Zhang et al., Cell Metabolism, 2021;33(4):833–844.e5; Adriaenssens et al., Cell Metabolism, 2019;30(5):987–996.e6).

Research status

GIP has never been developed as a drug in its own right; its clinical literature consists of physiology studies with native GIP infusions and receptor antagonists, plus industry programs built on engineered molecules.

The type 2 diabetes defect. The 1993 Göttingen clamp study compared synthetic human GIP and GLP-1 in nine people with mild type 2 diabetes and nine matched controls: the maximal GIP effect in the diabetic group was 54% lower than in controls, whereas GLP-1 retained most of its activity and also lowered glucagon (Nauck et al., Journal of Clinical Investigation, 1993;91(1):301–307). A Copenhagen study localized the defect to the late phase of insulin secretion, which GIP failed to amplify while GLP-1 normalized it (Vilsbøll et al., Diabetologia, 2002;45(8):1111–1119), and four weeks of near-normalized glucose roughly tripled the late-phase insulin response to GIP (Højberg et al., Diabetologia, 2009;52(2):199–207). These findings steered incretin drug development toward GLP-1 rather than GIP.

GIP receptor antagonist studies. The naturally occurring fragment GIP(3-30)NH2 was validated as a selective human GIP receptor antagonist in a crossover study of ten healthy men (NCT02747472): co-infusion reduced GIP-induced insulin secretion by 82% and removed the extra glucose requirement during a hyperglycemic clamp (Gasbjerg et al., Diabetologia, 2018;61(2):413–423). With that tool, endogenous GIP proved to matter more than endogenous GLP-1 for postprandial insulin in 18 healthy men: GIP blockade alone cut insulin secretion by about 30% and blockade of both hormones by 37% (Gasbjerg et al., Diabetes, 2019;68(5):906–917). In ten people with type 2 diabetes, GIP receptor blockade during a mixed meal reduced postprandial insulin by 14% and peak glucagon by 11%, left plasma glucose unchanged and roughly halved the postprandial suppression of bone resorption (Stensen et al., European Journal of Endocrinology, 2021;185(1):33–45).

Appetite and energy intake. In 17 overweight or obese men studied on five days with isoglycemic glucose infusions (NCT02598791), GLP-1 lowered ad libitum energy intake from 4,483 to 2,715 kJ, whereas GIP alone had no significant effect (4,062 kJ) and adding GIP to GLP-1 did not potentiate it; intake was higher with the combination than with GLP-1 alone (Bergmann et al., Diabetologia, 2019;62(4):665–675). Native GIP infusions do not reproduce the weight effects of GIP-receptor-active drugs.

Agonism versus antagonism. Mice lacking the GIP receptor were protected from diet-induced obesity and insulin resistance (Miyawaki et al., Nature Medicine, 2002;8(7):738–742), and antagonistic anti-GIPR antibodies reduced weight in obese mice and nonhuman primates, more so when co-dosed with a GLP-1 receptor agonist (Killion et al., Science Translational Medicine, 2018;10(472):eaat3392). Yet the dual agonist tirzepatide lowered glucose and body weight in type 2 diabetes from its first proof-of-concept study (Coskun et al., Molecular Metabolism, 2018;18:3–14); it engages the GIP receptor more than the GLP-1 receptor, mimics native GIP there, and in early trials outperformed selective GLP-1 receptor agonism (Willard et al., JCI Insight, 2020;5(17):e140532). In obese mice, its GIP receptor agonism produced weight-independent insulin sensitization (Samms et al., Journal of Clinical Investigation, 2021;131(12):e146353). A long-acting GIP receptor agonist tested as monotherapy, Lilly’s LY3537021, was studied in 85 healthy participants and people with type 2 diabetes (NCT04586907): it produced dose-dependent weight loss, 3.14 kg at the top dose in type 2 diabetes versus 0.36 kg on placebo at day 57, with a half-life of about 12 days, no delay in gastric emptying and infrequent gastrointestinal adverse events (Roell et al., Molecular Metabolism, 2026;103:102298). Zealand Pharma’s GIP receptor agonist ZP6590 entered a first-in-human trial in 88 participants on July 9, 2026, with primary completion estimated for September 6, 2027 (NCT07721597). On the antagonist side, Amgen’s maridebart cafraglutide, an anti-GIP receptor antibody conjugated to GLP-1 analog peptides, produced 12.3 to 16.2% weight loss at 52 weeks in 465 participants with obesity and 8.4 to 12.3% in 127 with obesity and type 2 diabetes, against 2.5% and 1.7% on placebo (Jastreboff et al., New England Journal of Medicine, 2025;393(9):843–857; NCT05669599); its phase 3 trial in 3,853 adults with obesity or overweight and without type 2 diabetes began on March 12, 2025 with primary completion estimated for January 21, 2027 (NCT06858839). Why both activating and blocking the receptor lower weight when paired with GLP-1 agonism remains unresolved (Nauck and Meier, Diabetes, Obesity and Metabolism, 2018;20(Suppl 1):5–21).

Ongoing physiology studies. As of November 2026, ClinicalTrials.gov lists investigator-led studies infusing native GIP, including a Rigshospitalet total-body PET study of glucose uptake and organ perfusion in 36 participants, recruiting since March 12, 2026 (NCT07398300). None is aimed at marketing approval.

Regulatory status. No GIP product is approved by the FDA or the European Medicines Agency, and Drugs@FDA and DailyMed list nothing for the molecule. The only approved drug that activates the GIP receptor is tirzepatide, approved by the FDA as Mounjaro on May 13, 2022 (NDA 215866) and as Zepbound on November 8, 2023 (NDA 217806) and authorized in the European Union on September 15, 2022.

Common dosage forms

• Research-grade lyophilized powder. Synthetic human GIP(1-42) in sealed vials labeled for laboratory research.
• Clinical-trial infusion solutions. GMP-grade synthetic GIP prepared by hospital pharmacies for investigator-led physiology studies, never marketed.
• No approved presentation. No pen, vial, tablet or compounded preparation of GIP has been approved anywhere.

Key considerations

• Regulatory status. The Research Market status reflects the absence of any FDA-approved, compounded or investigational drug product containing native GIP, as confirmed by Drugs@FDA and DailyMed. Human studies of the native hormone are academic physiology trials, and industry programs target the receptor with long-acting analogs or antibodies rather than with GIP itself.
• Native GIP is not a weight-loss or diabetes agent. Its insulinotropic effect is blunted in type 2 diabetes, it had no significant effect on energy intake in the controlled human infusion study, it raises glucagon at normal and low glucose, and intact peptide disappears from plasma in about seven minutes. The results of tirzepatide, retatrutide and maridebart cafraglutide do not transfer to the native hormone.
• The agonist-versus-antagonist question is open. Genetic and antibody data favor blocking the receptor, while the clinical record of tirzepatide and the phase 1 monotherapy data for LY3537021 favor activating it. Both strategies are in registered trials with primary completions listed for 2027.
• Bone and safety signals. Endogenous GIP accounts for about half of the postprandial fall in the bone-resorption marker CTX, so skeletal effects are a legitimate question for long-term GIP receptor antagonists. Native GIP infusions were well tolerated over hours, but no safety data exist for repeated or chronic exposure to the hormone.
• Naming. Gastric inhibitory polypeptide and glucose-dependent insulinotropic polypeptide are the same 42-residue peptide, abbreviated GIP; GIP(3-42) is its inactive DPP-4 metabolite and GIP(3-30)NH2 is a research antagonist. GIP is unrelated to gastrin-releasing peptide and to GLP-1, a separate incretin from a different gene.