CDK8 functions and regulation in diabetes
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Diabetic Dyslipidemia, Integrated Physiology\Fatty Acid Metabolism, Signal Transduction (Non-Insulin Action)\Transcriptional Regulation
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
The increasing prevalence of obesity and its related complications such as diabetes and insulin resistance has become a major public health concern. Dysregulation of lipid metabolism is closely associated with the development of these syndromes. One of the key regulators in lipid metabolism is the protein named SREBP-1c that functions to stimulate the expression of key genes involved in fatty acid biosynthesis. Previous studies have linked SREBP-1c to type 2 diabetes and its level is often elevated in diabetes. In preliminary studies, a novel regulator of SREBP-1c, called CDK8, which is a candidate gene implicated in type 2 diabetes, has been identified. CDK8 appears to be a key inhibitor of de novo lipogenesis. Interestingly, CDK8 protein is reduced in diabetes, inversely correlated with SREBP-1c levels and fatty liver phenotypes. Based on the preliminary observations, the proposed project is to study the relationship between these two proteins. A series of experiments are designed to elucidate whether and how CDK8 controls lipid metabolism in the liver by regulating SREBP-1c -mediated gene expression. State-of-art biological technologies will be applied to comprehensively dissect the role of CDK8 in diabetes. The objective of the proposed project is to characterize the molecular links between CDK8 and SREBP-1c in regulation of lipid metabolism, with a long-tem goal of determining whether this pathway can be targeted for preventing or treating type 2 diabetes and metabolic syndrome in humans.
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 is to study the regulatory mechanisms of lipid homeostasis in insulin resistance and type 2 diabetes. Dysregulation of lipid homeostasis is closely associated with obesity and type 2 diabetes. In insulin resistant states, both glucose and lipid production are constitutively high in liver and are refractory to regulation by insulin. Excessive lipid production causes fatty liver and hyperlipidemia, which can further exacerbate insulin resistance and lead to atherosclerosis and other cardiovascular complications. In this project, we are focusing on the regulation of proteins involved in lipid biosynthesis and their functions in diabetes. Charactering such proteins will help us understand the dysregulation of lipid homeostasis in type 2 diabetes and identify potential therapeutic targets for preventing or treating human diseases caused by aberrant lipid homeostasis.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
It has become clear that diabetes is far beyond a disease of blood sugar regulation. Lipid metabolism has intimate relationships with insulin resistance, in which insulin is unable to do its normal job of lowering blood sugar levels. Dysregulation of lipid homeostasis significantly contributes to the cardiovascular complications of diabetes. The prevalence of type 2 diabetes and insulin resistance is correlated with the increased incidence of obesity. Therefore, it is important to understand the molecular mechanisms of controlling lipid metabolism. The goals of our project are to elucidate the molecular mechanisms of regulating lipid biosynthesis in normal physiologic states and to determine the dysregulation of this process in insulin resistance and diabetic states. Our study has identified a novel regulator (named CDK8) of inhibiting lipid production. Consistent with the elevation of lipid production, this protein becomes less abundant in insulin resistant states and obesity. Our project will study the pathways that control the levels of this protein. Targeting such pathways may become an effective therapy to treat 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?
I started to become interested in diabetes research years ago when several of my relatives were diagnosed with type 2 diabetes. This complex disease is affecting more and more people worldwide largely due to the epidemic of obesity. Besides high blood levels of sugar, diabetes is also a major risk factor for cardiovascular disease. This association is a result of dyslipidemia in diabetes. Thus, understanding the regulatory mechanisms of lipid homeostasis is important for preventing and treating major human diseases including type 2 diabetes and cardiovascular disease. The primary interest of my laboratory is to understand the fundamental processes of gene expression. This award provides us the support to study the regulation of gene expression in relevance to lipid production and will enable us to make significant progress in this project.
In what direction do you see the future of diabetes research going?
Type 2 diabetes and obesity have become a major concern of public
health. Although the research in the past, especially recent years, has
dramatically improved our understanding on insulin resistance and
dysregulation of lipid metabolism, more studies are needed due to the
complex nature of the disease. It is important to understand the
molecular mechanisms that control the inter-relationship between glucose
and lipid metabolism in both normal and insulin resistant states. The
combination of improving both insulin sensitivity and lipid metabolism
would hold the promise of better treatments for type 2 diabetes.
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