GIP (Glucose-dependent Insulinotropic Polypeptide)

GIP (Glucose-dependent Insulinotropic Polypeptide, also called gastric inhibitory polypeptide) is a 42-amino acid incretin hormone secreted by K-cells of the duodenum and proximal jejunum in response to dietary fat and carbohydrate ingestion.

GIP was originally named for its ability to inhibit gastric acid secretion (at supraphysiological concentrations), but its primary physiological role is as an incretin — it potentiates glucose-stimulated insulin secretion from pancreatic beta cells. Together with GLP-1, GIP accounts for approximately 50-70% of total postprandial insulin secretion.

GIP's receptor (GIPR) is expressed not only on pancreatic beta cells but also on adipocytes, osteoblasts, cardiomyocytes, neurons, and immune cells, making GIP a pleiotropic metabolic regulator.

The historical view of GIP in type 2 diabetes was that it was "diabetogenic" because GIP's insulinotropic effect is blunted (GIPR resistance) in obese and type 2 diabetic individuals, while its adipogenic effects are preserved. This made GIP an unattractive drug target — until the discovery that GIPR agonism in the setting of GLP-1R co-agonism (as in tirzepatide) produces greater weight loss than GLP-1R agonism alone.

The SURPASS-2 trial (Frias et al., NEJM 2021) demonstrated that tirzepatide at 15 mg produced 2.4% greater HbA1c reduction and approximately 5 kg greater weight loss vs semaglutide 1 mg weekly. This superiority is widely attributed to tirzepatide's GIP receptor agonism, though the exact mechanism — whether central (hypothalamic GIPRs reducing food intake) or peripheral (adipose GIPR effects on fat redistribution) — remains an active area of research.

GIP research continues to expand beyond metabolic disease into bone health (GIPR deletion in mice reduces bone formation), cardiac protection (GIPR agonism reduces ischemia-reperfusion injury in animal models), and neuroinflammation.