The incretins are hormones that work to increase insulin secretion. The incretin concept was developed when it was observed that there is substantially more insulin secreted in response to oral glucose versus intravenous glucose, as shown in the graph at right. It was hypothesized that glucose in the digestive tract activates a feedforward mechanism that increases insulin secretion, anticipating the rise in blood glucose that would occur following 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 peptide hormones secreted by endocrine cells that are located in the epithelium of the small intestine.
Incretin hormone release is regulated in a similar way to other digestive tract hormones. An increase in the concentration of a substance in the lumen of the digestive tract (in this case glucose) acts as the trigger for hormone secretion.
The mechanism of incretin action is schematized in the figure below. Glucose in the small intestine stimulates incretin release. Incretins are carried through the circulation to their target tissue: the pancreatic beta cells. Incretin stimulation of beta cells causes them to secrete more insulin in response to the same amount of blood glucose.
There has been a lot of interest in developing incretin-based therapies for the treatment of type 2 diabetes mellitus (T2DM). T2DM is characterized by insulin resistance, which is a decreased responsiveness of tissues to insulin, and so it may lead to a relative insulin deficiency. Frequently, T2DM also involves defects in insulin secretion, particularly as the disease advances. There are several reasons why treatments with an incretin analogue, particularly a GLP-1 analogue, could be really beneficial.
In recent years, new incretin-based drugs have been developed and approved for the treatment of T2DM. These drugs are meant to be used in conjunction with other anti-diabetic drugs to help patients with T2DM who have had trouble maintaining adequate glycemic control.
One class of incretin-based drugs are the GLP-1 receptor agonists. These are peptide drugs that must be injected. The drugs are designed to be more stable than the native peptide, and resistant to degradation by DPP-4, the main protease that breaks down GIP and GLP-1.
The other class of drugs are DPP-4 inhibitors.
These drugs all have the suffix "-gliptin" in their name.
These drugs prolong the action of the native incretins by
preventing their breakdown. Although somewhat less effective
in promoting glycemic control as the GLP-1 agonists, an advantage
of the DPP-4 inhibitors is that they can be taken orally.