GIP

GIP (Glucose-dependent Insulinotropic Polypeptide) is a 42-amino acid incretin hormone secreted by enteroendocrine K-cells in the duodenum and jejunum in response to dietary fat and carbohydrates. Together with GLP-1, GIP accounts for 25–70% of the postprandial insulin response. It is one of the two receptor targets of tirzepatide (Mounjaro/Zepbound), the highest-efficacy approved obesity drug as of 2026.

GIP binds the GIPR, a class B GPCR, activating adenylate cyclase (cAMP) and calcium-independent phospholipase A2. In pancreatic beta cells, this potentiates glucose-stimulated insulin secretion (GSIS) while inhibiting glucagon from alpha cells. GIP also acts on adipocytes to promote lipid storage and on bone osteoblasts to regulate bone turnover. Glucose entry via SGLT1 in K-cells triggers KATP channel closure, membrane depolarization, and voltage-gated Ca2+ influx that drives GIP vesicle release.

GIP and GLP-1 co-agonism via tirzepatide has demonstrated superior glycemic control and weight loss vs. GLP-1 monotherapy in the SURPASS trials (HbA1c reduction 1.24–2.58%, body weight reduction 5.4–11.7 kg). Research into isolated GIP receptor agonism for obesity is ongoing; paradoxically, GIPR antagonism also produces weight loss, complicating the mechanistic picture. GIPR expression in the CNS and adipose tissue continues to be investigated.

Peptides commonly paired with GIP for synergistic effects.