Over a century ago, it was suspected that the lining of the gastrointestinal tract might make a substance that would stimulate the release of insulin from the beta cells of the pancreas. Numerous experiments were performed and published between 1906 and 1935 testing the effect of injected or ingested gut extracts on blood glucose levels of normal and diabetic animals and humans, but with contradictory results. In 1932, La Barre introduced the name "incrétine" (incretin) for this proposed substance. Many years later, in 1970, a polypeptide originally called "gastric inhibitory peptide" -- later renamed "glucose dependent insulinotropic polypeptide" (GIP) -- was recognized as being an incretin. Later, in 1985, another, called "glucagon-like peptide 1" (GLP-1), was identified.

Incretins are hormones

These two incretins are peptides that are made in the gut. They are now recognized as hormones that enhance the secretion of insulin in response to glucose. In other words, nutrients within the gut cause release of these incretin hormones from the lining of the gut, which thereafter travel by blood to the pancreatic islet cells, where they stimulate the release of insulin. They also have other actions, such as inhibiting the postprandial (after meal) release of glucagon. Both GIP and GLP-1 are rapidly inactivated by an enzyme called dipeptidyl peptidase-IV (DPP4).

GIP is made in the upper part of the small intestine. There are receptors for GIP in the islets of the pancreas, and also in the stomach, adipose tissue, brain, and elsewhere. GLP-1 is made in both the small and large intestine, as well as by other tissues including neurons in the brain. There are receptors for GLP-1 in the islets of the pancreas, lungs, brain, skeletal muscle and kidney.

Using the incretins as therapy for diabetes

Two classes of medications have been developed that take advantage of the incretins to treat diabetes. Several GLP-1 receptor agonists and several DPP-4 inhibitors are now available for the treatment of patients with type 2 diabetes, and many more are in development.

GLP-1 receptor agonists

It was found that GLP-1 itself had a very short duration of action, so it wasn't very promising as a medication for diabetes. However, drugs have been developed that work by activating the GLP-1 receptors. These drugs are called "GLP-1 receptor agonists" or, for short, "GLP-1 agonists."

The first of these medications was found in the late 1980s, when Dr. John Eng, an endocrinologist at the Bronx VA Medical Center in New York, performed studies confirming that venom from a lizard called the Gila Monster stimulated the production of insulin. Dr. Eng's compound was subsequently synthesized and developed by Amylin Pharmaceuticals, and is now marketed as Byetta (exenatide).

Other companies are also developing similar drugs, including Victoza (liraglutide) from Novo-Nordisk, which is approved for use in Europe. Long-acting versions of these drugs are also being investigated, with several that would allow once-weekly dosing. It has also been found that the GLP-1 receptor agonists are unlikely to cause hypoglycemia, unless used in combinations with other drugs that do cause hypoglycemia (such as the sulfonylureas).

DPP-4 inhibitors

Since the active version of the incretins are inactivated by the enzyme DPP-4, it would seem reasonable to think that if a drug could be developed that would inhibit the inactivator, then the incretin would remain more available to produce its effects. It was indeed found that using DPP-4 inhibition produces approximately a doubling of circulating incretin hormones, and as a result, there is better control of blood glucose. It was also found that these drugs are unlikely to cause hypoglycemia.

The available DPP-4 inhibitors include Januvia (sitagliptin), Onglyza (saxagliptin), and Galvus (vildagliptin) (Galvus is approved in Europe but not the US).

Comparison of the GLP-1 receptor agonists and DPP-4 inhibitors

A recent review article compared the clinical characteristics of these two classes of medications
(Efficacy and safety of incretin based therapies: Clinical trial data. White J. J Am Pharm Assoc 2009)

Summary

The incretins are gastrointestinal hormones that influence insulin secretion, and which have been the basis for the development of new medications for type 2 diabetes.