Glucose-dependent insulinotropic polypeptide (revision 71)

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]

GIP receptors are expressed on pancreatic beta cells, enteroendocrine cells, neural tissue and adipocytes. Beyond the beta cell, GIP inhibits gastric acid secretion and slows gastric emptying. In adipose tissue, GIP promotes triglyceride uptake and storage — a pathway that was hypothesised to mediate the modest weight gain sometimes observed in early GLP-1 monotherapy and is now thought to explain some of the superior weight loss seen with dual agonists, if GIP signal inhibition at the adipocyte level reduces energy storage.^[3]

In type 2 diabetes, the incretin effect is attenuated primarily because beta cells are unresponsive to GIP — even pharmacological GIP concentrations fail to stimulate insulin secretion, whereas GLP-1-directed drugs remain effective. This loss of GIP potency has been termed GIP-incompetence and is distinct from deficient GIP secretion, which does not occur. The mechanism remains unclear; current hypotheses include altered receptor expression, impaired downstream signalling and altered beta-cell function secondary to chronic hyperglycaemia.^[1]

In obesity without diabetes, fasting GIP is elevated and the postprandial response is exaggerated, particularly to fat ingestion. Whether this hyperresponse contributes to weight gain or is a consequence of it remains unresolved. The observation that dual GIP/GLP-1 agonists produce greater weight loss than GLP-1 monotherapy is sometimes attributed to active GIP-receptor antagonism at the adipocyte, though the evidence remains limited.^[3]

GIP remained therapeutically unexploited for decades because insulinotropic beta-cell responses were thought to be lost in diabetes; the development of GLP-1-directed monotherapy proceeded from that understanding. Dual GIP/GLP-1 receptor agonists (tirzepatide, retatrutide) have demonstrated superior glycaemic control and weight loss compared to GLP-1 monotherapy in phase 3 trials, and are now approved or in development for both type 2 diabetes and obesity.^[3][4]

The mechanisms underlying dual-agonist superiority are incompletely understood. Hypotheses include restoration of beta-cell GIP responsiveness through ambient GLP-1 signalling, adipose-tissue effects of dual agonism, and effects on the feeding centre in the hypothalamus. The GIP effect appears to be weight-loss dependent rather than independent, suggesting complementary rather than additive mechanisms.

• Glucagon-like peptide-1
• GLP-1 receptor
• Incretin effect
• Dipeptidyl peptidase-4
• Dual incretin agonist
• Beta cell function

• Seino S, Fukushima M, Yabe D. "GIP and GLP-1, the two incretin hormones: Similarities and differences." Journal of Diabetes Investigation 1(3):8–23 (2010).

• GIP — Gene entry — NCBI Gene record for the GIP gene.