Niswender, Kevin , MD, PhD
GLP1 receptor modulators for diabetes and obesity
General Research Subject: Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology
Type of Grant: Basic Science
Project Start Date: January 1, 2010
Project End Date: December 31, 2012
A new class of medicines for diabetes that are peptide activators of the glucagon-like peptide-1 receptor (GLP1R) are effective at lowering blood glucose in patients with diabetes and induce healthy weight loss. GLP-1 is a naturally occurring hormone that has similar effects but is rapidly degraded in the body. Basic science studies also show that GLP1R activation stabilizes or increases the number of insulin producing cells, whereas they normally die off in diabetes. Thus, for the first time in the treatment of diabetes, there is significant hope that this type of medicine may change the progressive course of diabetes for the better.
An opportunity exists to develop medicines that activate GLP1R, but that are chemicals that can be taken in a pill instead of injected with a needle. We believe that this will have additional advantages because small molecules (chemicals) can be designed to turn on the receptor in new ways and doing this may greatly increase the effectiveness of the medicine and also reduce significant side effects from the injectable medicine, such as nausea and vomiting. We have already identified chemicals that possess these properties by a process called high-throughput screening. The goal of this project is to study these chemicals, find the best ones that work in unique ways, and optimize them using chemistry techniques to make them even better, and ultimately test the effects of this approach in animal models of diabetes. This would represent a fundamentally new way to treat diabetes and potentially obesity.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project covers the development of new medications to potentially capitalize on new ways to treat diabetes. Thus this is a therapy related research project.
The goals of this project are to develop new ways to treat diabetes. The exciting possibility about this approach is that by therapeutically targeting the glucagon-like peptide-1 system, which we are trying to do in a novel way, may change the course of diabetes and/or may contribute to preventing diabetes in the first place. Clearly these goals are a long way off, but we seek to try a new approach to get to these goals.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We are hoping to improve on existing therapies that are already quite effective for treating diabetes, namely the injectable drug exenatide, which improves blood sugar control, but also which appears to help control weight gain. We are hoping to develop a medicine that could be taken as a pill rather than an injection and that would activate the same receptor that exenatide does, but do it in a different way and in a way that might have more potent effects. We are also hoping that such an approach could minimize the side effects that are frequently seen when taking a medicine like exenatide. We are in the very early stages of using novel concepts in the development of medicines that activate receptors like the GLP-1 receptor.
There is a lot of excitement in the research field right now that medicines like exenatide, and newer medicines that target the same system, will prevent weight gain, improve diabetes control, and hopefully keep the pancreatic beta cells metabolically healthy The hope is that by getting the right medicine to the right patient we can ultimately prevent their pancreatic beta cells from declining to function and thereby change the natural history of the disease, make diabetes much easier to control, and ultimately improve long term outcomes for patients with diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been involved in diabetes research for over 20 years now, throughout my entire training and my still early independent research career. Diabetes affects so many people, and in my clinical practice I see the devastating effects that living with uncontrolled diabetes for many, many years has on many people. Living with diabetes is an enormous challenge for many patients, and anything we can do to develop new treatments to make controlling diabetes easier and to prevent complications is well worth our efforts.
This research award will play a critical role in our research efforts to both develop new medicines and to understand more how the GLP-1 receptor works to control diabetes and appetite. We are using several unique ideas, and the project remains in early phases. Because of this, our project that has both a high risk profile (we don't know for sure that we will succeed) and the potential for very high reward (being a better understanding of how the GLP-1 receptor works and/or promising compounds for further development to treat diabetes). Of course, the pathway to ultimately create a new medicine to treat any disease, including diabetes, is long, arduous, and fraught with challenges. Many other research funding mechanisms do not support such high risk research projects. It is our hope that with these funds generously awarded by the ADA we will be able to advance this project to the point where the significant additional funding necessary to actually generate medicines to treat people with diabetes will be seen as a logical next step rather than a high-risk next gamble.
In what direction do you see the future of diabetes research going?
There are clearly a number of areas in which diabetes research is expanding rapidly. First is the development of new types of medicines to treat diabetes and these include those that target the GLP-1 system, as we propose to do herein. Thus the identification of new targets and ways to treat diabetes is clearly one important future area.
Next, clearly we need to begin to focus on prevention. The ability to identify individuals at high risk for diabetes and the ability to implement interventions that prevent progression is critical to halt the ongoing diabetes epidemic. To some extent, the promise of some of these new medications to keep beta cells healthy and to prevent weight gain may play some role in this area also.
Lastly, I see a clear need for diabetes research in the area of teaching. As leaders and diabetes care providers we need to understand better how to deliver diabetes care, how to better teach our patients to administer self-care, and how better to teach our medical trainees and primary care colleagues to better care for people with diabetes.
One of my own research interests that touches, to some extent, on the prior three points, is the role of the brain in the development and treatment of diabetes. While the brain is not classically thought to be an 'insulin sensitive' organ, insulin and GLP-1 both have interesting roles in the brain that are and will remain the focus of much research.
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