Huo, Yuqing , MD
Macrophage A2AR regulates glucose homeostasis
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology
Type of Grant: Basic Science
Project Start Date: January 1, 2010
Project End Date: December 31, 2013
Metabolic disorders are closely associated with inflammation. Adenosine plays an important role in regulating inflammation processes through adenosine receptor A2A. We have recently found that A2AR deficiency aggravates high fat diet (HFD)-induced hyperglycemia and insulin resistance in mice, and administration of a specific A2AR agonist in mice protects mice from HFD-induced insulin resistance. These observations suggest that A2AR regulates glucose homeostasis and insulin sensitivity. However, the mechanisms underlying this effect are unknown. Macrophage A2AR is important for the inhibitory effect of adenosine on inflammation. In addition, liver, adipose tissue and skeletal muscle are major organs involved in the initiation and development of metabolic disorders.
We propose macrophage A2AR plays a pivotal role in modulating inflammatory and metabolic responses of the liver, adipose tissue as well as skeletal muscle, and as such regulates systemic glucose metabolism and insulin sensitivity. To test this hypothesis, we will use specific A2AR agonists, complete A2AR-deficient (A2AR--/--) mice, and mice lacking A2AR on macrophages (Mac-A2AR--/-- mice) to study inflammation and metabolic changes in adipose, liver and skeletal muscle. The results from this study will not only elucidate how A2AR regulates glucose homeostasis but also provide a basis for application of A2AR agonists in the treatment of metabolic disorders.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My project will study the mechanisms for the development of type 2 diabetes. Diabetes associated disorders such as obesity, heart attack and stroke are the most common causes of morbidity and mortality in industrialized (and some developing) countries. Studying the underlying mechanisms that are responsible for the development of type 2 diabetes is crucial for the development of treatments for these diseases. In recent years, the role of inflammation in metabolic abnormalities such as hyperglycemia and insulin resistance has become a highlight in the field of research. Adenosine receptor 2A (A2AR) has been intensively studied for its role in inflammation. However, to date, there is no study on the role of A2AR in the regulation of glucose homeostasis. Our preliminary evidence suggests that A2AR participates in the regulation of glucose homeostasis.
We will use integrative approaches involving 'loss-of-function' and the 'gain-of-function' experiments to define the mechanisms underlying the role of macrophage A2AR in the regulation of glucose homeostasis. The results from this study will not only elucidate how A2AR regulates glucose homeostasis but also provide a basis for application of A2AR agonists in the treatment of metabolic disorders.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project will first elucidate how A2AR regulates glucose homeostasis. And then antagonists of A2AR will be tested in diabetic mice for their efficacy in the treatment of type 2 diabetes. Very likely, these A2AR agonists will be eventually applied to diabetic patients to lower down their blood glucose levels, to reduce inflammation, and consequently to decrease the incidence of diabetic complications.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My primary research interest focuses on the inflammatory aspect of atherosclerosis. Diabetes is one of major causes for atherosclerosis. Also it is recently suggested the type 2 diabetes is associated with a low grade inflammation. Thus, it is scientifically important to determine whether the inflammation I am studying in the filed of atherosclerosis is also crucial for the development of type 2 diabetes. I have been interested in extending my research expertise to the field of diabetic research for years.
This award provides the support and also offers me an opportunity to extend my expertise in the field of inflammation to the diabetic research. Thus, this award will significantly enrich and expand my research scope. With a success in completion of this project, we will be more close to the real mechanisms for the development of type 2 diabetes. As a result, a novel approach for the treatment of type 2 diabetes will be developed.
In what direction do you see the future of diabetes research going?
Inflammation is one of important directions for diabetes research. Recent studies have revealed the close association of inflammation and diabetes. However, it is still unclear whether inflammation is an initiator or just an accelerator for the development and progression of diabetes. Also many mysteries remain regarding the types of inflammatory factors and pathways employed by those inflammatory factors in the development and progression of type 2 diabetes. Thus, much effort is required in this direction in the field of diabetes research.
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