Incretins

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 activated a feedforward mechanism that increased 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 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.

• Defective incretin action in T2DM. Many type 2 diabetics show deficient insulin secretion in response to meals.  This may be due to a lack of an effect of incretins. Studies have shown that in type 2 diabetics, there is less GLP-1 secretion, and beta cells are less responsive to GIP.
  
• Glucose-dependent effect on insulin secretion. Incretins work to increase insulin secretion, but do it in a way that is glucose dependent. The incretins do not by themselves stimulate much insulin secretion, rather they work to augment glucose-stimulated insulin secretion. T2DM drugs that increase insulin secretion, such as the sulfonylureas and meglitinides, may cause hypoglycemia because they stimulate insulin secretion regardless of blood glucose concentration. A drug that mimics an incretin shouldn't have this effect.
• Other effects of GLP-1 beneficial for the treatment of T2DM. In addition to glucose-dependent stimulation of insulin secretion, GLP-1 has other effects that help to lower blood glucose and contribute to glycemic control. GLP-1 inhibits glucagon secretion. Glucagon is a hormone that works oppositely to insulin, increasing blood glucose by stimulating glucose production by the liver. GLP-1 delays stomach emptying, which helps to spread glucose absorption out over time, and thus limit hyperglycemia. Patients using the incretin-based drug exenatide (see below) tend to lose weight; this is probably related to delayed stomach emptying.  Furthermore, studies in animals have shown that GLP-1 can increase the number of beta cells, either through promoting growth or by inhibiting apoptosis.

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. Exenatide (Byetta®; approved in April of 2005) is a peptide GLP-1 receptor 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 major 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 once-daily dosing.  Another class of drugs are the specific inhibitors of DPP-4; these drugs have the suffix "-gliptin" in their name.   These drugs prolong the action of the native incretins by preventing their breakdown.  Drugs that have gained FDA approval are:  sitagliptin (Januvia®; approved in October of 2006), saxagliptin (Onglyza®; approved in July of 2009), and linagliptin (Tradjenta®; approved in May of 2011) .  An advantage of DPP-4 inhibitors is that they can be taken orally, unlike the GLP-1 agonists, which are peptides and must be injected.