FAQ: What impact do newer classes of drugs, such as the incretins, have on insulin secretion by the beta cells?

Frequently asked questions for the primary care community, excerpted from a conversation between a leading primary care physician and a world-renowned beta cell researcher. (3:45)


Dr. Leahy: Think about using and designing therapies in a disease based on a preferred treatment profile, not just blood glucose lowering, but also from a pathophysiology point of view.  And that’s actually so interesting in the diabetes world because we have all these new classes of diabetes drugs and we’ve had these older classes, some of them for 50 years, the reality is we really didn’t get agents to use that were designed from the get-go to do something important based on what we knew about diabetes.  

Most of these drugs until about ten years ago were drugs that pharmaceutical companies just almost accidentally discovered lowered blood sugars in some kind of model and then they evolved into treatments for diabetes -- not insulin obviously, but many of our traditional drugs -- even TZDs quite frankly.  And then we -- ten years ago pharmaceutical companies got very interested in the incretin system and started to ask, “Gee, I wonder if we have agents that work on the incretin system that would be a useful drug therapy?”  And the short answer is ten years later they are useful and we have agents in the clinic, but again they sort of started from a design -- wouldn’t it be interesting to see if X happens if we use a drug in that direction -- and that’s our future.  Many of the drugs, or most of the drugs, that will come to us in the future someone decided based on basic science as an important thing to test that ended up being a useful outcome and we’ll get that drug. 

So incretins, what are incretins? Incretins are this hugely important physiological system in all of us that helps to control blood sugars after meals.  It is the dominant physiological system in that regard.  So if anyone goes out and stops and has a spectacular lunch or supper with lots of calories and carbohydrates and enjoys their meal, if they don’t happen to have a problem with glucose tolerance and their blood sugars are pretty normal after that meal, they should thank the incretin system.  Because the incretin system is essentially a physiologic connection from the gut and the brain telling islets, “Hey, food is coming, you need to respond appropriately which is to put out more insulin and also turn off glucagon –- two of the key incretin hormones.” 

The reason the incretin system is so important is that first of all there are a number of dimensions of that system that have been identified physiologically and are good drug targets.  One of them happens to be something called DPP-4 – dipeptidyl peptidase-4 –- which is an enzyme which acts to normally inhibit and to turn off the action of these important incretin hormones.  So you can take a drug that’s slows or stops the metabolism so that the incretin system works either better or longer.  The second is one of the key incretin hormones called GLP-1 -- glucagon-like peptide-1.  It turns out that there are drugs now out there that either look like GLP-1 or bind to GLP-1 receptors and, thus, just essentially replicate this incretin affect. 

The second issue of the incretin system was of interest some years ago and continues to be of interest is because these hormones that are released from the GI tract when we eat and promote these islet effects that I told you, the system is wounded in Type II diabetes -- it’s reasonably defective.  There is clearly defective incretin regulation that occurs somewhere during the process of the disease and we believe that is part of the impaired islet function -- the beta cell dysfunction -- and the failure to turn off glucagon at a meal promoting post-meal hyperglycemia in patients with this disease and so if that’s true, getting agents which actually work on that system predictably would be a positive and they are a positive.  Again, if you look at the drug classes we have, they help to control post-meal blood sugars just in the way it would have been predicted.