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DPP-4 Inhibitors

by Mark T. Marino, MD

In 2006, a new class of medicine for Type 2 diabetes was introduced to the U.S. market. Called DPP-4 inhibitors, these drugs work in a way that is different from any previous diabetes treatment. Sitagliptin (brand name Januvia) was the first drug in this class to be approved; it can be used alone or in combination with other oral diabetes drugs. Saxagliptin (Onglyza), another DPP-4 inhibitor, received approval in July 2009.

Research history
At the turn of the 20th century, several different researchers were examining the role of the intestines and the pancreas in diabetes. Research soon demonstrated, through experiments with animals and autopsies of people who had died of diabetes complications, that Type 1 diabetes was caused by a problem with the pancreas. After extracts of the pancreas were shown to treat diabetes, a research team at the University of Toronto (Frederick Banting and Charles Best) isolated insulin in 1921.

Further experiments went on to explore the relationship between the pancreas and the intestines. Some of these demonstrated that intestinal extracts could lower blood glucose by stimulating the pancreas to produce more insulin. Hormones from the intestines with this effect are called incretins. Significant research on incretins was not conducted again until the 1960’s, when researchers were faced with a puzzle: When people were given the same amount of glucose at different times by vein and by mouth, the amount of insulin produced was much greater when the glucose was given by mouth. The researchers concluded that the gastrointestinal tract was signaling the pancreas to produce insulin. The hunt was on for the exact chemicals involved in this process, and finally a hormone was isolated: gastric inhibitory polypeptide, or GIP. A second hormone called glucagon-like polypeptide 1, or GLP-1, was later isolated.

GLP-1 was found to have a profound effect on stimulating the release of insulin from the pancreas. It was also found to be active for a very short time in the blood. This is because it is broken down quickly by an enzyme called dipeptidyl peptidase 4, or DPP-4. A drug that could inhibit the action of DPP-4 would extend the insulin-releasing effect of GLP-1.

Function in the body
Drugs that inhibit the action of DPP-4 are intervening in a complex set of reactions that occur when food is eaten. In response to meals, specialized cells in the intestines called L cells secrete GLP-1. L cells are mainly found in the ileum, the last segment of the small intestine, and in the large intestine (also known as the colon). GLP-1 appears to be secreted, however, before food from a meal reaches these areas of the intestines. The L cells have receptors for a variety of hormones secreted by the digestive system, which helps them determine the type of nutrients that have been consumed and control the amount of GLP-1 they release. It is thought that hormonal signals from the upper intestine, as well as a chemical released by nerves in response to eating, stimulate the release of GLP-1.

GLP-1 has several effects in the body other than stimulating the release of insulin. It also slows stomach emptying, inhibits the release of glucagon (glucagon is a hormone that signals the liver to release glucose and is usually elevated in people with Type 2 diabetes), and enhances the survival and growth of pancreatic beta cells, which secrete insulin. It has been found in laboratory studies that animals treated with DPP-4 inhibitors seem to have an increased number of pancreatic beta cells, indicating that these drugs may stimulate beta-cell growth (most likely through the action of GLP-1). This effect has not yet been demonstrated in humans, but if confirmed, it means that DPP-4 inhibitors could play a significant role in delaying and possibly reversing the progression of Type 2 diabetes.

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