Treatments for diabetes have one goal: to get sugar out of the blood and into tissues. Insulin plays a critical role in this process by promoting the uptake and storage of glucose and indeed most therapies focus on increasing insulin levels.

Incretins are hormones secreted by the gut when we eat. They do a variety of things that help remove blood sugar. Pancreatic beta cells have receptors for this hormone and will secrete more insulin in response to its binding to these receptors. It also promotes the growth of additional beta cells. This is a fantastic boon for patients in the early stages of type 2 diabetes who still have functioning beta cells as it will prolong pancreatic function.

Incretins also inhibit glucagon release. Glucagon is a surprisingly important hormone for diabetes patients. People who are in the process of developing type 2 diabetes actually have more insulin than normal because they are insulin resistant. The body senses that it is not getting enough glucose (since insulin does not seem to be doing its job) and promotes the biosynthesis of more glucose in the liver. The hormone that triggers this is glucagon. How much glucose is contributed by the liver? Measurements indicate that it can be equal to what one takes in during a meal. This is pretty significant. So, by inhibiting glucagon secretion, incretins inhibit the pathological biosynthesis of unnecessary glucose.

Incretins also slow gastric emptying. This is important as one of the problems faced by people with diabetes is that when they eat too fast, they overwhelm the system with glucose and the body cannot handle it. By decreasing the rate at which the stomach dumps food into the intestines (gastric emptying) incretins allow the body to keep up. As an added benefit, this slowing of gastric emptying promotes a feeling of satiety. If you feel less hungry you eat less and this, of course, is very helpful for people with diabetes.

All of these wonderful benefits would suggest that we give people with diabetes tons of incretins. However, there are a few issues. Firstly, if one takes too much it promotes nausea and vomiting. Not good. Secondly, the body does not want to have these proteins around forever and has a way of degrading them. This ends up being quite useful as it gives us an interesting way to modulate incretin levels. What if, instead of giving a person a shot of incretin hormone, we somehow inhibited the degradation pathway? This idea was attempted and it worked beautifully.

The main incretin hormone goes by the name, GLP-1 (we scientists love acronyms – it’s a disease unto itself). Since GLP-1 is a small protein (called a polypeptide) it is degraded by a protease enzyme. We have quite a few protease enzymes in our stomach. This one is a bit special in that it is not found in the stomach and it only cleaves certain peptide bonds associated with certain hormones. The protease is called DPP-4. What researchers have found is that we can inhibit DPP-4 with certain compounds. These compounds are now being used to treat diabetes under the trade names Januvia and Onglyza.

Another polypeptide, found in the saliva of the Gila monster (of all places), is called exendin-4 and has the property of binding to our GLP-1 receptors and activating them to some extent. Importantly, it is not cleaved by DPP-4. A polypeptide based on this lizard hormone is now being marketed as Byetta.

As with incretins, Byetta can still cause significant nausea and vomiting. Interestingly, while Januvia still causes some adverse gastrointestinal effects it seems to occur about 3 times less often than Byetta when looking at clinical trial data. It would be worth trying a DPP-4 inhibitor if you have found extendin-4 causes too much GI discomfort. Incretin based therapies are not for everyone but they do add another dimension to the diabetes treatment universe and that is a good thing.