Rader, Daniel J., MD
Role of Arv1 in glucose homeostasis
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Adipocytes, Diabetic Dyslipidemia, Integrated Physiology\Insulin Resistance
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2009
Project End Date: June 30, 2013
Dr. Steve Sturley of Columbia University discovered a novel gene in yeast he called ARV1 that is involved in sterol metabolism and showed that it is widely expressed in mammals. The function of ARV1 in mice has been studied by selectively and partially reducing protein expression of this gene in liver. These mice had a decrease in serum glucose level but an increase in lipids. Additional experiments have shown that ARV1 works to move the intracellular cholesterol to the cell membrane.
Therefore, deficiency of this gene results in lipid accumulation inside the cells, which triggers cell stress and inflammation. Type 2 diabetes is associated with insulin resistance essentially in all organ systems including muscle, liver, fat, and pancreatic beta cell. Although much has been learned about the mechanism of diabetes, the role of fat in insulin sensitivity and development of diabetes is not clear. The hypothesis is that lipid accumulation inside the fat cells caused by ARV1 deficiency will lead to inflammation and cell stress, which pose a threat to normal cell functions including lipid storage and secretion of various factors which are involved in insulin sensitivity. All these steps eventually lead to insulin resistance and type 2 diabetes. Mice with specific deficiency of ARV1 in fat will be used to test this hypothesis.
Mentor: Daniel Rader, MD Postdoctoral Fellow: Kazuhiro Nakaya, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our project is focused on the interaction between lipid/cholesterol disorders and diabetes. This project will contribute to our understanding of diabetes, its treatment and prevention. We discovered a specific gene known as ARV1. When it doesn't work well, normal lipid metabolism is disrupted. Our theory is abnormal lipid accumulation in fat tissue leads to inflammation and cell stress. When this occurs, it poses a threat to normal cell functions including lipid storage and secretion of various cell factors which are involved in insulin sensitivity. All these steps eventually lead to development of insulin resistance and type II diabetes. We generated mice with disruption of ARV1 gene specifically in fat tissue. We hope to utilize this animal model to understand the underlying mechanism and to explore the possibility of developing a new therapeutic plan to prevent the progression of lipid disorders and type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetes is a group of diseases that lead to high blood glucose levels due to defects in either insulin secretion or insulin action in the body. Our current understanding is both genetics and environmental causes such as obesity and lack of exercise appear to play roles. Although much has been learned about the mechanism of diabetes, the role of fat tissue in insulin sensitivity and development of diabetes is not clear. Fat tissue is a complex metabolic and endocrine organ. In our current project we intend to discover why people with lipid disorders are predisposed to diabetes. We have generated a new mouse model which has a deficiency in lipid metabolism in fat. We hypothesize that lipid accumulation inside the fat cells will lead to inflammation and cell stress, which pose a threat to normal cell functions including lipid storage and secretion of various factors which are involved in insulin sensitivity. Lipid abnormalities in fat tissue eventually lead to insulin resistance and type 2 diabetes. Our study will allow us to relate abnormal glucose metabolism to the underlying proteins and genes in fat tissue we are studying. In other words, we will study the potential clue to the link between fat and diabetes. Ultimately, our goal is to find out better treatment and prevention again lipid disorders and diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
When patients have diabetes, they are more likely to have cholesterol abnormalities, which contribute to cardiovascular diseases including atherosclerosis. On the other hand, obesity and other lipid disorders could cause insulin resistance and type 2 diabetes. I believe the best way to treat diabetes would be to prevent it in the first place. My laboratory is interested in genetic and inflammatory factors that regulate the lipid and lipoprotein metabolism and molecular relationship to atherosclerosis and diabetes. I was well aware of the many funding opportunities available from the ADA Research Foundation. This grant will allow us to carry out our original study on a novel gene involved in lipid metabolism and glucose homeostasis. Thanks to the ADA Mentor-Based Postdoctoral Fellowship Award, I am training a postdoctoral fellow Fumin Tong, M.D., PhD, in the area of lipid metabolism and diabetes. Specifically, we are studying how the lipid accumulation in fat leads to changes in glucose metabolism, and why lipid disorders are associated with insulin resistance and type 2 diabetes.
In what direction do you see the future of diabetes research going?
Metabolic Syndrome (Syndrome X) has been defined as a cluster of at least 3 of 5 criteria: insulin resistance and glucose intolerance, obesity, high blood pressure, low HDL (high-density lipoprotein, good cholesterol) cholesterol, and high triglycerides. Alterations in plasma lipid levels such as high cholesterol and fatty acids are risk factors to the various metabolic diseases including atherosclerosis, stroke, obesity and insulin resistance. Our lab is working to delineate molecular regulation of lipid and lipoprotein metabolism related to the mechanisms of various metabolic diseases including diabetes. All the above factors are intercalated and contribute to the development of these diseases. Therefore, studies on gene-gene and gene-environment interactions would provide us invaluable evidence to better understand the mechanism of these diseases and come up with new prevention and treatment approaches for diabetes.
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