They are hormones that work to increase insulin secretion.
The concept of incretin was developed when it was observed that there is substantially more insulin secreted in response to oral glucose versus intravenous glucose.
It was hypothesized that glucose in the digestive tract activated a feeding mechanism that increased insulin secretion, anticipating the increase in blood glucose that would occur after absorption of ingested carbohydrates.
There are two main incretin hormones in humans, GIP (glucose-dependent insulinotropic peptide, also known as gastric inhibitory peptide) and GLP-1 (glucagon-like peptide-1).
Both hormones are secreted by endocrine cells that are located in the epithelium of the small intestine. Incretin hormone release is regulated similarly to other hormones in the digestive tract.
An increase in the concentration of a substance in the lumen of the digestive tract (in this case, glucose) acts as a trigger for the secretion of the hormone.
Glucose in the small intestine stimulates the release of incretin. Incretins are carried through the circulation to their target tissue: pancreatic beta cells.
Incretin stimulation of beta cells causes them to secrete more insulin in response to the same amount of glucose in the blood.
There has been great interest in developing incretin-based therapies for the treatment of type 2 diabetes mellitus (DM2).
T2DM is characterized by insulin resistance, which is a decrease in the responsiveness of tissues to insulin, which can lead to a relative insulin deficiency.
T2DM also often involves defects in insulin secretion, particularly as the disease progresses. There are several reasons why treatments with an incretin analog, particularly a GLP-1 analog, could be really beneficial.
Defective incretin action in T2DM
Many type 2 diabetics show poor insulin secretion in response to meals. This may be due to the lack of an effect of the incretins.
Studies have shown that in type 2 diabetics, there is less GLP-1 secretion, and beta cells are less sensitive to GIP.
Glucose-dependent effect on insulin secretion
Incretins work to increase insulin secretion, but do so in a glucose-dependent way. Incretins by themselves do not stimulate much insulin secretion, but instead work to increase glucose-stimulated insulin secretion.
T2DM medications that increase insulin secretion, such as sulfonylureas and meglitinides, can cause hypoglycemia because they stimulate insulin secretion regardless of blood glucose concentration.
A drug that mimics an incretin should not have this effect.
Other beneficial effects of GLP-1 for the treatment of DM2
In addition to stimulating glucose-dependent insulin secretion, GLP-1 has other effects that help lower blood glucose and contribute to glycemic control. GLP-1 inhibits glucagon secretion .
Glucagon is a hormone that works in the opposite way to insulin, which increases blood glucose by stimulating glucose production in the liver. GLP-1 slows stomach emptying, which helps spread glucose absorption over time and therefore limits hyperglycemia.
Patients using the incretin-based drug exenatide tend to lose weight; this is probably related to a delay in stomach emptying.
Additionally, animal studies have shown that GLP-1 can increase beta cell numbers, either by promoting growth or by inhibiting apoptosis.
Incretin and drugs
In recent years, new drugs based on incretins have been developed and approved for the treatment of DM2.
These medications are intended to be used in conjunction with other antidiabetic medications to help T2DM patients who have had trouble maintaining proper glycemic control.
Exenatide (Byetta®, approved April 2005) is a GLP-1 receptor peptide agonist that was originally isolated from lizard venom.
Exenatide is more effective than native GLP-1 because it is more stable: it is resistant to degradation by DPP-4, the main protease that breaks down GIP and GLP-1.
Liraglutide (Victoza® approved in January 2010) is another GLP-1 agonist drug that is even more stable and offers the advantage of a daily dose.
Another class of drugs are the specific DPP-4 inhibitors; these drugs have the suffix “-gliptin” in their name. These drugs prolong the action of native incretins by preventing their degradation.
The drugs that have obtained FDA approval are: Sitagliptin (Januvia®, approved in October 2006), Saxagliptin (Onglyza®, approved in July 2009), and Linagliptin (Tradjenta®, approved in May 2011).
An advantage of DPP-4 inhibitors is that they can be taken orally, unlike GLP-1 agonists, which are peptides and must be injected.