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Wikipedia - Incretin

GLP-1 and DPP-4 inhibitors

Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even 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. As expected, 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 glucagon-like peptide-1 (GLP-1) and Gastric inhibitory peptide (aka glucose-dependent insulinotropic polypeptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

GLP-1 (7-36) amide is not very useful for treatment since it must be administered by continuous subcutaneous infusion. Several long-lasting analogs that have insulinotropic activity have been developed and two, exenatide (Byetta) and liraglutide (Victoza), have been approved for use in the U.S. The main disadvantage of these GLP-1 analogs is that 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 a tablet have been developed. One of them, Januvia (sitagliptin) was approved by the FDA on October 18, 2006.

Contents

[edit] History

In 1902, Bayliss and Starling proposed that intestinal mucosa contains a hormone that stimulates the exocrine secretion of the pancreas ("Secretin").

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 possible therapy for diabetes. In 1939–1940, based on their studies, Leow et al. concluded that the existence of incretins was “questionable.” No further research in this area was performed for about thirty years.

[edit] Recent research

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 that 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. It was found that only one specific sequence of GLP-1 has 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).

[edit] See also

  • exenatide - first drug that utilises the "incretin effect"

[edit] References

  • http://www.glucagon.com
  • Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes, Lancet 2006;368:1696-705

[edit] Further reading

  • Nielson, Loretta L. (15 May 2005), "Incretin mimetics and DPP-IV inihibitors for the treatment of type 2 diabetes", Drug Discovery Today, Reviews (Elsevier) 10 (10/24): 703–710 
    Includes table describing an overview of type 2 diabetes drug therapies; 76 references.
Retrieved from "http://en.wikipedia.org/wiki/Incretin"

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Incretin".

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