Incretin
Encyclopedia
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
released from the beta cells of the islets of Langerhans
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
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
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
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
Glucagon-like peptide-1
Glucagon-like peptide-1 is derived from the transcription product of the proglucagon gene. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The biologically active forms of GLP-1 are: GLP-1- and GLP-1-NH2...
(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
Dipeptidyl peptidase-4
Dipeptidyl peptidase-4 , also known as adenosine deaminase complexing protein 2 or CD26 is a protein that, in humans, is encoded by the DPP4 gene.-Function:...
(DPP-4).
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 two, exenatide
Exenatide
Exenatide is a medication approved in April 2005 for the treatment of diabetes mellitus type 2. It belongs to the group of incretin mimetics and is manufactured by Amylin Pharmaceuticals and Eli Lilly and Company....
(Byetta) and liraglutide
Liraglutide
Liraglutide , marketed under the brand name Victoza, is a long-acting glucagon-like peptide-1 analog that has been developed by Novo Nordisk for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency on July 3, 2009, and by the U.S...
(Victoza), 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 a tablet have been developed. One of them, Januvia (sitagliptin
Sitagliptin
Sitagliptin is an oral antihyperglycemic of the dipeptidyl peptidase-4 inhibitor class. It was developed, and is marketed, by Merck & Co...
) was approved by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
on October 18, 2006.
History
In 1902, Bayliss and Starling proposed that the intestinal mucosa contains a hormone, secretinSecretin
Secretin is a hormone that controls the secretions into the duodenum, and also separately, water homeostasis throughout the body. It is produced in the S cells of the duodenum in the crypts of Lieberkühn...
, that stimulates the exocrine secretion of the pancreas.
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.
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 GIP stimulates insulin secretion. However, initial research could not establish its utility as a treatment for diabetes. The anglerfishAnglerfish
Anglerfishes are members of the teleost order Lophiiformes . They are bony fishes named for their characteristic mode of predation, wherein a fleshy growth from the fish's head acts as a lure; this is considered analogous to angling.Some anglerfishes are pelagic , while others are benthic...
proglucagon
Proglucagon
Proglucagon is a protein that in humans is encoded by the GCG gene.Proglucagon is a precursor of glucagon, and several other components. It is generated in the alpha cells of the pancreas and in the intestinal L cells in the distal ileum and colon...
peptide was sequenced in 1982 by Lund and co-workers. The human proglucagon
Proglucagon
Proglucagon is a protein that in humans is encoded by the GCG gene.Proglucagon is a precursor of glucagon, and several other components. It is generated in the alpha cells of the pancreas and in the intestinal L cells in the distal ileum and colon...
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).
See also
- exenatideExenatideExenatide is a medication approved in April 2005 for the treatment of diabetes mellitus type 2. It belongs to the group of incretin mimetics and is manufactured by Amylin Pharmaceuticals and Eli Lilly and Company....
- first FDA approved drug that uses the "incretin effect" - liraglutideLiraglutideLiraglutide , marketed under the brand name Victoza, is a long-acting glucagon-like peptide-1 analog that has been developed by Novo Nordisk for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency on July 3, 2009, and by the U.S...
- second FDA approved drug that uses the "incretin effect"
External links
- Glucagon.com - site of Dr D.J. Drucker's laboratory that studies incretins