Lynch, Ronald M, PhD
Multivalent GLP-1 Analogs for Beta-Cell Targeting and Therapy
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications, Integrated Physiology, Integrated Physiology\GLP-1, GIP, and Other Gut Hormones, Islet Biology\Signal Transduction
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Dysfunction and loss of pancreatic beta-cells is the primary cause of Diabetes Mellitus. Clinical intervention largely focuses on controlling blood glucose after beta-cell demise. Early diagnosis of beta-cell decline (pre-diabetes) will allow interventions to maintain beta-cell mass (BCM), rather than replacement after they are lost. However, to date, all approaches used to monitor BCM in humans have been unsuccessful. The primary limitation is an inability of contrast agents used for imaging to discriminate between beta-cells and other cells, because BCM is small relative to other abdominal tissue (liver, intestine) such that only a small amount of contrast agent uptake by these tissues overwhelms the beta-cell signal.
Our previous research demonstrates that cell type discrimination can be greatly enhanced with molecules that bind simultaneously to more than one cell surface target, particularly if the two receptors as a combination are unique to that cell type; a bar code per se. One promising beta-cell target is the glucagon-like protein 1 receptor (GLP-1R). We will focus on two hypotheses: (1) that molecules based on GLP-1 can be produced that will bind with significantly higher affinity to beta-cells expressing the GLP-1R, and (2) that a true beta-cell specific agent can be developed by producing a ligand against two surface proteins that, as a combination, are unique to beta-cells. The agents developed with support from ADA will have unique properties that will provide an entirely new class of agents for specific targeting beta-cells with the goal of use for non-invasive analysis of BCM in humans
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
The drug development we propose will have a role in the treatment of both type 1 and type 2 diabetes, and long term may have efficacy in treatment of diabetic complications. The loss of function and number of pancreatic beta-cells is the ultimate cause of uncontrolled type 1 and type 2 Diabetes. Glucagon like peptide-1 (GLP-1) has been proven to enhance both function and the mass of beta -cells, and is currently being used clinically to treat diabetes Moreover, GLP-1 has been modified to produce several stable analogs, such as clinically proven Exenatide or Liraglutide.
Although these drugs hold great promise for treatment of diabetes, our work will continue development of new GLP-1 like agents that will be specific for beta -cell thereby limiting off-target complications, and also may have potential for oral intake which is not currently possible for existing GLP-1 analogs that need to be injected.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The pharmaceuticals we intend to develop should improve the insulin secretion capability in response to changes in blood glucose, while having minimal side effects. Moreover, our goal is to design and synthesize an orally available GLP-1 like agent that will not need to be injected as current GLP-1 analogs require.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Personally, I have several friends with children afflicted with type 1 Diabetes, so I am very familiar with the difficulties of dealing with diabetes daily. With the epidemic rise in type 2 diabetes, I believe that controlling this disease will become a predominant problem for health care in our country over the coming decades.
This award from the ADA provides my collaborative research group with an opportunity to begin studies that will provide a unique approach to develop drugs for treatment and analysis of beta-cell dysfunction. However, once we prove that our approach to development of this unique class of drugs is proven, we expect that similar approaches can then be taken to develop targeted drugs for treatment of diabetic complications as well.
In what direction do you see the future of diabetes research going?
There are several primary directions that appear clear.
- Diagnosis. Genetic testing coupled with sensitive analytical testing for propensity to development diabetes is required prior to initiation of treatment, and to follow treatment efficacy.
- Blockade of development of Diabetes. For type 1, the determination of auto-immune mechanisms will be used to develop patient specific approaches to block disease development. For type 2 diabetes, a much longer horizon is apparent, with a possible analogy to cancers were underlying causes may be resolved to many different mechanisms. This will require multiple approaches to reversing the development of type 2 diabetes, including nutritional and exercise based interventions
- Pharmacology: treatment. As described in our proposal, new technologies are being developed that may provide tissue type specific treatment thereby decreasing off target effects (complications) and allowing for better patient specific treatments.
- Technology/device development will allow for better maintenance and control of blood glucose in patients that have fully developed disease.
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