Lee, Jongsoon , PhD
The role of circulating monocytes in the development of obesity-induced insulin resistance
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, 2012
It is now well accepted that obesity induces inflammation in adipose tissue (AT) and that this may promote the development of systemic insulin resistance. It is currently believed that obesity -induced AT inflammation is predominantly driven by particular immune cell types called macrophages. However, macrophages cannot proliferate and this suggests that increased macrophage populations in obese animals and human require influx of a precursor form of macrophages. These cells are called monocytes and they can be found in blood.
Therefore we hypothesized that obesity activates circulating blood monocytes first, and then activated monocytes can move into adipose tissue and become macrophages. We further hypothesize that if we can block these processes, we can suppress monocyte immobilization and eventually obesity-induced inflammation and insulin resistance. We will test these hypotheses by using several animal models including genetically engineered animals and anti-inflammatory drug, a high dose of salicylate. Our findings from the proposed studies will show the role of monocytes in obesity-induced inflammation and insulin resistance for the first time and may provide a valuable drug target for the treatment of insulin resistance and Type 2 Diabetes in human.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
It is increasingly accepted that inflammation plays a role in the development of obesity-induced insulin resistance and Type 2 Diabetes (T2D). However, the underlying molecular mechanism by which inflammation participates in the development of obesity-induced insulin resistance is not yet fully understood. One question in particular is, 'Where is obesity-induced inflammation initiated?' Currently, there is evidence that adipose tissue macrophages may play a significant role in initiating the inflammation. This suggests that obesity alters circulating monocyte (macrophage precursor) phenotypes, thereby changing adipose tissue macrophage numbers and functions. This further suggests that suppression of circulating monocyte inflammation may inhibit adipose tissue macrophage functions, and that this, in turn, may improve systemic insulin sensitivity. We will test this hypothesis by analyzing the circulating monocytes and adipose tissue macrophages using various genetic and pharmacological animal models with different immunological techniques.
This project will determine whether circulating monocytes initiate the development of obesity-induced inflammation and, therefore, mediate the development of systemic insulin resistance. Hence, outcomes of this project will provide evidence supporting the notion that circulating monocytes are a valuable target for the treatment of insulin resistance.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Recent findings strongly suggest that inflammation plays a role in mediating the development of obesity-induced insulin resistance. Clinical trials further show that suppression of inflammation improves insulin sensitivity in Type 2 Diabetes patients. In this project, we hope to determine the cellular target of obesity-inflammation and anti-inflammatory interventions. These findings will help the development of anti-inflammatory drugs that specifically target a subset of immune cells for the treatment of insulin resistance and Type 2 Diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Several of my family members already have Type 2 Diabetes. Moreover, as the prevalence of diabetes is alarmingly increasing, my friends and more family members are becoming diabetic. Recently, my brother-in-law was diagnosed as insulin resistant, and my only advice to him was to exercise more and watch his diet. Although lifestyle modification is the best treatment for insulin resistance and Type 2 Diabetes, it is difficult to sustain the same level to keep the development of diabetes in check. This project examines a new cellular target for the treatment of Type 2 Diabetes. Therefore, I hope that our research helps to identify the immunological etiology of obesity-induced insulin resistance and to eventually control glucose homeostasis in Type 2 Diabetes patients. Since immunological dysregulation is not universally accepted as a cause of insulin resistance yet, funding opportunity is limited. Thus, this funding will timely provide necessary support to test a new hypothesis for the role of circulating monocytes in the development of obesity-induced insulin resistance.
In what direction do you see the future of diabetes research going?
Classically, it is believed that dysfunctions of insulin-responsive tissues such as fat, liver, muscle and ß-cells cause insulin resistance. Although numerous studies strongly support this and contributions of these tissues for glucose homeostasis is still very important, recent findings are starting to show that other tissues/cells also play important roles in glucose homeostasis. Those include brain, gut and various immune cells.
I expect that we will see more research investigating how tissue/cell cross-talk can regulate systemic glucose homeostasis in animals and humans and how dysregulation of these cross-talks can cause the development of obesity-induced insulin resistance and Type 2 Diabetes. From these studies, I expect more developments of new classes of investigative drugs to specifically target these tissues for the treatment of insulin resistance and Type 2 Diabetes.
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