GIP (Glucose-Dependent Insulinotropic Polypeptide)

Deep dive

GIP (Glucose-Dependent Insulinotropic Polypeptide): complete reference

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino-acid incretin hormone secreted by intestinal K-cells in response to nutrient intake — particularly fat and glucose. Like GLP-1, GIP stimulates pancreatic beta-cell insulin secretion in a glucose-dependent manner. Unlike GLP-1, however, GIP does not significantly inhibit glucagon or slow gastric emptying in patients with type 2 diabetes; in fact, GIP signaling is often blunted in T2D. The therapeutic interest in GIP comes from research demonstrating that dual GIP + GLP-1 receptor agonism (as in tirzepatide) produces greater weight loss and glycemic improvement than GLP-1 monotherapy. The precise mechanism by which GIP contributes to weight loss is still being characterized — proposed mechanisms include adipose-tissue lipid handling, central nervous system effects on appetite, and synergy with GLP-1 signaling at shared downstream pathways. Selective GIP agonists are an emerging research area; oxyntomodulin-based triple agonists (GIP + GLP-1 + glucagon) like retatrutide showed even greater weight loss in Phase 2 trials.

In practice

When you take Mounjaro or Zepbound, the medication activates BOTH the GLP-1 receptor (familiar from Ozempic) AND the GIP receptor — this dual activation is what makes tirzepatide more effective than semaglutide on average.

Clinical context

Dual GIP/GLP-1 mechanism is the basis for tirzepatide's superior efficacy. Triple agonists (adding glucagon) are in Phase 3 trials.