Glucose-dependent insulinotropic polypeptide (revision 16)

Glucose-dependent insulinotropic polypeptide (GIP), also termed glucose-dependent insulinotropic peptide, is a 42-residue peptide hormone secreted by enteroendocrine K cells of the duodenum and proximal jejunum in response to the ingestion of glucose, fat and amino acids. It is one of the two principal incretin hormones, the other being Glucagon-like peptide-1 (GLP-1).^[1]

GIP is processed post-translationally from pro-GIP and circulates in two forms: the active GIP (1–42) and an N-terminally cleaved GIP (3–42) produced by dipeptidyl peptidase-4 cleavage. Both forms retain insulin-secretory activity, which is unusual among incretin peptides and is the basis for the glucose-dependent descriptor — GIP potentiates insulin secretion only when glucose is elevated.^[2]

The historical naming reflects its dual function: it inhibits gastric acid secretion (the basis of the original acronym, glucose-dependent insulinotropic peptide) and amplifies postprandial insulin secretion. In type 2 diabetes, the insulinotropic arm of GIP is impaired, whereas the GLP-1 arm remains partly intact, which is why GLP-1-directed therapies were developed first. The later discovery that dual GIP/GLP-1 receptor agonism produces greater clinical benefit than GLP-1 monotherapy has reestablished GIP as a therapeutic target.^[3]

GIP is encoded by the GIP gene and is processed from a 153-residue pro-GIP. Like GLP-1, it is subject to tissue-specific post-translational modification. In K cells, endopeptidases cleave pro-GIP to release the active hormone. The principal stimuli are glucose and long-chain fatty acids; amino acids are a weaker stimulus.^[1]

K cells are found predominantly in the duodenum and jejunum, extending into the ileum in smaller numbers. They are open-type epithelial cells with an apical surface exposed to the lumen, allowing direct contact with nutrient-induced secretagogues. Secretion is biphasic: an early phase within 15 minutes of ingestion, followed by a later more sustained phase as nutrients pass through the intestine.^[1]

Fasting concentrations of total GIP in healthy adults are typically 40–60 pmol/L, rising 5–10-fold postprandially. The response to glucose is monophasic, reaching a peak around 30–60 minutes after a meal. This distinct timing profile — earlier than GLP-1 and independent of the distal small intestine — means GIP is the first incretin to encounter the portal circulation.

GIP acts through the GIP receptor (GIPR), a class B G-protein-coupled receptor structurally related to the GLP-1 receptor. Like GLP-1, GIP coupling is glucose-dependent at the beta cell: the same concentration of GIP that stimulates insulin secretion at 8 mM glucose is ineffective at 2 mM, the physiological basis for avoiding hypoglycaemia in the fasting state.^[3]