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Incretin Hormone

A hormone that stimulates insulin secretion in response to meals. The two most important incretin hormones are called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Understanding how these hormones work is helping to yield new treatments for Type 1 and Type 2 diabetes.

The whole concept of incretin hormones comes from a decades-old observation that orally administered glucose provokes a far greater release of insulin than the same amount of glucose delivered by injection. Scientists postulated that there must be some signal from the gastrointestinal tract (or “gut”) that increases insulin release whenever food is consumed. A considerable amount of evidence now suggests that GLP-1 and GIP are responsible for most of this increased insulin release. Furthermore, scientists have also observed that people with Type 2 diabetes have diminished insulin release in response to meals and have speculated that they may have defects in the release or action of their incretin hormones.

GLP-1 is made in the small intestine and colon and is released in response to food. It stimulates insulin secretion in a glucose-dependent manner — that is, it stimulates insulin secretion only when there is glucose in the bloodstream. GLP-1 has other beneficial effects as well: It delays stomach emptying, which slows the absorption of carbohydrate and the resulting rise in blood glucose level after meals; it curbs appetite; and animal studies have shown that it may promote regeneration of the pancreatic beta cells and fight apoptosis (programmed cell death), improving the survival of existing beta cells.

GIP is made by cells in the upper small intestine and is released when glucose comes in contact with these cells. Like GLP-1, GIP affects the pancreatic beta cells, where it stimulates insulin secretion, and also appears to promote beta cell proliferation and beta cell survival.

Naturally, all of these effects have prompted drug companies and medical researchers to create drugs that act like incretin hormones or affect their biochemical pathways. For example, they have discovered a substance in Gila monster venom called exendin-4, which acts similarly to human GLP-1 but is much longer-acting. Amylin Pharmaceuticals and Eli Lilly and Company developed a synthetic version of exendin-4 called exenatide (brand name Byetta), which received marketing approval in April of 2005 as an adjunctive treatment for Type 2 diabetes that is not adequately controlled by metformin, a sulfonylurea drug (such as glyburide, glipizide, or glimepiride), or both. The manufacturers also developed Bydureon, a formulation of exenatide that needs to be injected only once a week instead of twice a day. Novo Nordisk has created liraglutide (Victoza), a GLP-1 analog for people with Type 2 diabetes that is injected once a day, and a number of other drug companies also have GLP-1 analogs under development.

Researchers have tried infusing GIP into people with Type 2 diabetes, with varying results. In some cases, insulin secretion was increased, but in others, little or no extra insulin was secreted at all.

Another class of drugs called DPP-IV inhibitors also affect incretin hormone levels. Dipeptidyl peptidase IV (or DPP-IV) is an enzyme that normally breaks down GLP-1 and GIP. DPP-IV inhibitors, which block the action of this enzyme and therefore leave more of the body’s own GLP-1 and GIP in circulation. DPP-IV inhibitors, which include sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta), have been shown to improve blood glucose control, enhance the insulin secretory response, and increase insulin sensitivity.



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