Glucose-dependent insulinotropic polypeptide (revision 27)
Old revision·19:43, 7 Dec 2024·KPV_Kester
| Glucose-dependent insulinotropic polypeptideIncretin hormone | |
|---|---|
GIP is a 42-residue peptide processed from pro-GIP in the duodenum and proximal jejunum. | |
| Abbreviation | GIP |
| Precursor | Pro-GIP (gene GIP) |
| Principal source | Intestinal K cells (duodenum, proximal jejunum) |
| Molecular data | |
| Residues | 42 |
| Monoisotopic mass | ≈4,972 Da |
| Plasma half-life | 7 minutes |
| Receptor | |
| Target | GIP receptor (GIPR) |
| Receptor family | Class B secretin-like GPCR |
| Principal coupling | Gs → adenylyl cyclase |
| Topic infobox · conventions | |
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]
Biosynthesis and secretion
[edit]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.
Receptor signalling and cellular actions
[edit]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]
See also
References
- ^ a b c Nauck MA. "Incretin hormones: Their role in health and disease." Diabetes, Obesity and Metabolism 20 Suppl 1:4–21 (2018). DOI:10.1111/dom.13129. PMID 29364588.
- ^ Deacon CF, Johnsen AH, Holst JJ. "Degradation of glucose-dependent insulinotropic polypeptide by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo." Journal of Clinical Endocrinology and Metabolism 80(3):952–957 (1995). PMID 7883856.
- ^ a b c Frías JP, Davies MJ, Rosenstock J, et al. "Tirzepatide versus semaglutide oral in type 2 diabetes." New England Journal of Medicine 385(6):503–515 (2021). DOI:10.1056/NEJMoa2107519. PMID 34170647.