GIP

Glucose-Dependent Insulinotropic Polypeptide

GIP (glucose-dependent insulinotropic polypeptide, formerly known as gastric inhibitory polypeptide) is an incretin hormone secreted by enteroendocrine K-cells in the duodenum and proximal jejunum. Like GLP-1, GIP is released in response to food intake and acts to potentiate glucose-dependent insulin secretion from pancreatic beta cells. However, GIP has a distinct and broader biological profile that extends well beyond the pancreas.

GIP receptors are expressed in adipose tissue, bone, the central nervous system, and the cardiovascular system, among other organs. In adipose tissue, GIP promotes lipid storage and influences adipocyte function, which has historically made it a controversial target in obesity research. Some early studies suggested that blocking GIP signaling could reduce fat accumulation, but more recent evidence, including data from tirzepatide (a GIP/GLP-1 dual agonist), has demonstrated that GIP receptor agonism can paradoxically enhance weight loss when combined with GLP-1 receptor activation. The precise mechanism behind this effect remains an area of active investigation, with hypotheses including enhanced central satiety signaling and improved adipose tissue function.

In the context of retatrutide, GIP receptor agonism is one of the three receptor pathways targeted by the molecule. The inclusion of GIP activity is thought to complement GLP-1 effects on appetite and glycemic control while providing additional metabolic benefits through its effects on fat tissue and energy balance. Like native GLP-1, endogenous GIP is rapidly degraded by DPP-4, with a half-life of approximately seven minutes in its active form.

The role of GIP in metabolic disease continues to be elucidated, and GIP receptor agonism represents one of the newer frontiers in incretin-based therapeutics. Its inclusion in multi-receptor agonists like retatrutide and tirzepatide underscores the evolving understanding that targeting multiple hormonal pathways can produce synergistic metabolic benefits.