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 are continuing to study the effects of exenatide in people with diabetes and are testing a new formulation that needs to be injected only once a week instead of twice a day. Novo Nordisk is testing another long-acting GLP-1 analog called liraglutide in people with Type 2 diabetes, and a number of other drug companies also have GLP-1 analogs under development.
The National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring a clinical trial to study the effects of exenatide in people who have had Type 1 diabetes for several years but whose pancreases still make some insulin. The trial is designed to determine whether exenatide can help the pancreas generate new beta cells and make more insulin.
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.
Other experimental 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. A number of pharmaceutical companies are working on DPP-IV inhibitors, which block the action of this enzyme and therefore leave more of the bodyís own GLP-1 and GIP in circulation. DPP-IV inhibitors have been shown to improve blood glucose control, enhance the insulin secretory response, and increase insulin sensitivity in animal and human studies. In rats with chemically induced diabetes (a model of Type 1 diabetes), DPP-IV inhibitors increased the number of pancreatic islets and beta cells. More, longer-term studies of DPP-IV inhibitors in humans are now under way.
