Holz, George Gilbert, PhD
Role of cAMP sensor Epac2 in islet insulin secretion
General Research Subject: Type 2 Diabetes
Focus: Islet Biology, Islet Biology\Channels, Single Cell Studies, and Calcium Signaling, Islet Biology\Hormone Secretion and Exocytosis, Islet Biology\Signal Transduction
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Type 2 diabetes mellitus (T2DM) is a metabolic disorder of systemic glucose homeostasis that is treatable with newly developed blood glucose-lowering agents that reproduce the antidiabetogenic actions of an incretin hormone known as GLP-1. The research proposal described here seeks to use genetically engineered mice and donor human islets of Langerhans in order to establish how one such agent (BYETTA) stimulates the secretion of insulin from pancreatic beta cells. In this regard, we will determine whether the cAMP sensor Epac2 mediates beneficial actions of BYETTA to restore defective glucose-stimulated insulin secretion from the pancreata of patients diagnosed with T2DM.
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 concerns our interest in determining exactly how the incretin hormone GLP-1 stimulates the secretion of insulin from the endocrine pancreas. This is an important topic to address because GLP-1 is the prototype of a new class of blood glucose-lowering agents that include the incretin mimetic exenatide, and the GLP-1 analog liraglutide. Our studies lead us to propose that the cAMP-binding protein Epac2 mediates the action of GLP-1 to upregulate insulin secretion from pancreatic beta cells. Thus, the research funded by this ADA Research Grant Award will reveal an underlying mechanism of drug action that is important to the therapy of type 2 diabetes mellitus, while also establishing Epac2 to be a likely molecular target for future drug discovery efforts.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We are testing our hypothesis that the cAMP-binding protein Epac2 is a suitable molecular target for pharmacological intervention in the treatment of type 2 diabetes mellitus. We are also seeking to determine how GLP-1 receptor agonists such as exenatide or liraglutide exert their Epac2-mediated actions to stimulate the secretion of insulin from pancreatic beta cells. It is our contention that new small molecule compounds can be identified that activate Epac2 directly. Assuming so, we expect to be able to derive new pharmacological agents that exert potent blood glucose-lowering effects in patients with type 2 diabetes mellitus.
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 the last 22 years. This interest is an outcome of my recognition that diabetes is a particularly serious public health problem that needs to be addressed through basic research that will ultimately lead to the discovery of new medications that can either prevent or ameliorate the symptoms of diabetes. This new ADA Research Grant Award will play an especially important role in furthering my research efforts since it will provide critically important funding for the next 3 years.
In what direction do you see the future of diabetes research going?
1. I expect that an orally-administrable form of the GLP-1-based family of blood glucose-lowering agents will soon be discovered. Research will be directed at identifying such agents.
2. I expect that the GLP-1-based class of blood glucose-lowering agents will be increasingly prescribed by clinicians. I also expect that these same agents will be shown to be valuable for the treatment of obesity and cardiovascular disorders. Research will be directed at defining the multiple actions of GLP-1 that are relevant to the treatment of diabetes within the context of obesity and heart failure.
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