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The Incretins: GLP-1 Agonists and DPP-4 Inhibitors

In 1902, Researchers first hypothesized that the gut might directly signal the pancreas. Later in 1930, the term incretin was first used to describe the enhanced glucose lowering effect that was seen when a gut extract was fed to dogs. In the 1960s, researchers discovered that almost twice as much insulin was released when they infused glucose directly into the gut rather than into the blood as an IV solution. This discovery of an increase in insulin release renewed interest in a search for compounds produced by the gut that could lower blood glucose levels.

The first incretin to receive FDA approval in May of 2005 was Byetta. Byetta is a GLP-1 like drug or agonist and is rather unusual in that it is derived from a compound found in the saliva of the Gila monster, a large lizard native to the southwestern US. It is currently available as a prescription for people with Type 2 diabetes who are not on insulin.

GLP-1 or glucagon-like peptide 1 is one of several incretin compounds that have biologic activity. After release into the blood by the intestine in response to food intake, GLP-1 slows food absorption. This delay in absorption allows the slow insulin response found in Type 2 diabetes to catch up. Improved insulin production also occurs when people take GLP-1 agonists. Both an increase in beta cell mass and improvement of first phase insulin release toward normal have been seen with this drug. Researchers hope that this action may delay progression of Type 2 diabetes or possibly assist in recovery of beta cell activity in early Type 1 diabetes. GLP-1 agonists have multiple sites of action.

So far, the reduction of glucose levels, blood pressure, and weight plus an increase in well being all appear positive. Side effects like nausea that does not go away on minimal doses may require that the medication be stopped or that smaller starting doses be given with a syringe rather than using the standard starting dose of 5 mg that is provided in the Byetta pen.

In addition to the delay in food absorption, GLP-1 agonist also stimulate insulin production and restore first phase insulin secretion. The overall effect is to decrease the postmeal blood sugars and improve control without the risk of hypoglycemia. Research has shown that people on Byetta eat about 20% less and often lose weight.

Giving natural GLP-1 was found to have little benefit because it is broken down by an enzyme called DPP-4 (dipeptidyl peptidose IV) within about 5 minutes. This lead to a search for modified GLP-1 molecules like Byetta, produced by Amylin and Lilly, that are not broken down as quickly. Other new GLP-1 derivatives are currently in clinical trials. These include liraglutide by Novo-Nordisk and DAC:GLP-1 by Conju Chem.

Related to the GLP-1 agonists is a second new class of diabetes medications called DPP-4 Inhibitors which work by delaying the breakdown of GLP-1, as well as other incretins. Because DPP-4 is involved in the break down of several peptides in the body, it will take time to be sure there are no unwanted long-term side effects.

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