Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins do so by causing an increase in the amount of insulin released from pancreatic beta cells of the islets of Langerhans after eating, before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. They also inhibit glucagon release from the alpha cells of the islets of Langerhans. The two main candidate molecules that fulfill criteria for an incretin are the intestinal peptides glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (also known as: glucose-dependent insulinotropic polypeptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4); both GLP-1 and GIP are members of the glucagon peptide superfamily.
"Many factors stimulate insulin secretion, but the main one is blood glucose. Incretins, especially GIP and GLP-1 secreted, respectively, by K and L cells in the gut are also important", (Rang and Dale's Pharmacology (2015)).
GLP-1 (7-36) amide is not very useful for treatment of type 2 diabetes mellitus, since it must be administered by continuous subcutaneous infusion. Several long-lasting analogs having insulinotropic activity have been developed, and three, exenatide (Byetta) and liraglutide (Victoza), plus exenatide extended-release (Bydureon), have been approved for use in the U.S. The main disadvantage of these GLP-1 analogs is they must be administered by subcutaneous injection.
Another approach is to inhibit the enzyme that inactivates GLP-1 and GIP, DPP-4. Several DPP-4 inhibitors that can be taken orally as tablets have been developed.
However, oral administration of extracts of intestinal mucosa failed to help several patients with type 1 diabetes. In 1932, La Barre proposed the name incretin for a hormone extracted from the upper gut mucosa, which caused hypoglycemia, and proposed a possible therapy for diabetes. In 1939–1940, based on their studies, Leow et al. concluded the existence of incretins was "questionable". No further research in this area was performed for about thirty years.
In 1970, GIP was isolated and sequenced from intestinal mucosa (JC Brown). Originally named gastric inhibitory peptide, GIP was renamed glucose-dependent insulinotropic peptide in 1973 after Brown and Dupre showed GIP stimulates insulin secretion. However, initial research could not establish its utility as a treatment for diabetes. The anglerfish proglucagon peptide was sequenced in 1982 by Lund and co-workers. The human proglucagon gene was cloned in 1983 by G. Bell, et al., and the human proglucagon sequence was subsequently deduced. However, the entire GLP-1 molecule had no effect on insulin levels. Only one specific sequence of GLP-1 was found to have an insulinotropic effect: GLP-1 (7-36) amide. It is rapidly inactivated to GLP-1 (9-36) by DPP-4 with a plasma half-life of only 1–2 minutes. GIP is also rapidly inactivated by DPP-4 to GIP (3-42).
- Glucagon-like peptide-1 analogs ("incretin mimetics")
- Glucagon.com - site of Daniel J. Drucker's laboratory that studies incretins
- Drucker DJ, Nauck MA (November 2006). "The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes". Lancet 368 (9548): 1696–705. doi:10.1016/S0140-6736(06)69705-5. PMID 17098089.
- Amori RE, Lau J, Pittas AG (July 2007). "Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis". JAMA 298 (2): 194–206. doi:10.1001/jama.298.2.194. PMID 17622601.
- Bayliss W, Starling EH (Sep 12, 1902). "The mechanism of pancreatic secretion" (PDF). J. Physiol. (London) 28 (5): 325–353. doi:10.1113/jphysiol.1902.sp000920. PMC 1540572. PMID 16992627.