Project title
糖尿病與代謝症候群致病機轉的研究
Internal ID
NSC101-2314-B002-069-MY3
Principal Investigator
Start Date
August 1, 2012
End Date
July 12, 2013
Investigators
Organizations
Partner Organizations
A Study on the Pathogenesis of Diabetes and Metabolic Syndrome = 糖尿病與代謝症候群致病機轉的研究
Description
Objective: To predict diabetes in the future by traditional risk factors, 50% of high-risk subjects will not be identified, based on our preliminary results. Therefore, this project aims to improve the definition of high-risk group by serum biomarkers. The first part of this project is to search for potential serum markers which can predict the development of diabetes and metabolic syndrome in the future, including serum vascular adhesion protein-1 (VAP-1, not vascular cellular adhesion molecule, not VCAM-1) and serum metabolites found by metabolomics (specific aim 1A& 1B). Besides, we will also establish a cohort which has been followed for 5 years, to analyze the relationship of hemoglobin A1c to diabetes, chronic kidney disease, and atherosclerosis in carotid arteries in the future (specific aim 1C). This can provide evidence to support the definition of diabetes and pre-diabetes in Taiwan. The second part of the project is to investigate the role of VAP-1 in the pathogenesis of obesity and diabetes.We will study the relationship between the expression of VAP-1 in omental and subcutaneous adipose tissue, obesity, and insulin resistance, and analyze the relationship between serum VAP-1 and area of visceral and subcutaneous fat in human subjects (specific aim 2A & 2C). Since monocyte chemotactic protein-1 (MCP-1) and adiponectin is involved in the pathogenesis of diabetes, we will also explore the relationship between the expression of VAP-1, MCP-1 and adiponectin in human adipose tissues (specific aim 2A). Besides, we will also analyze the change of serum VAP-1 during follow-up, and correlate with the change of obesity, insulin secretion function, and insulin resistance in human (specific aim 2D).We will study if serum VAP-1 changes in response to rosiglitazone treatment in subjects with diabetes (specific aim 2E). In cell models, we will investigate if VAP-1 can regulate the expression and secretion of MCP-1 and adiponectin in adipocytes and macrophages (specific aim 2B). Research design and methods: In specific aim 1A, we will measure serum VAP-1 by time-resolved immunofluometric assay to analyze if serum VAP-1 can predict the development of diabetes and metabolic syndrome in 2 years in a cohort study. In specific aim 1B, we will measure metabolites by LC-QTOF MS and GC-TOF MS, and search for potential metabolites to predict diabetes and metabolic syndrome by nested case-control design. In specific aim 1C, we will follow a cohort at 5 years, and to know their health status by questionnaires, physical examination, blood tests, and urinary tests. In specific aim 2A, subjects receiving scheduled surgery will by recruited in a cross-sectional study. Their omental and subcutaneous adipose tissue will be collected. Protein and RNA will be extracted. Expression of VAP-1, MCP-1, and adiponectin will be analyzed and correlate with clinical characteristics. In specific aim 2B, inhibitors of VAP-1 or recombinant mouse VAP-1 will be added to evaluate if VAP-1 can regulate the expression and secretion of MCP-1 and adiponectin in 3T3-L1 adipocytes and RAW macrophages by autocrine or paracrine effect. In specific aim 2C, we will measure serum VAP-1 and compute the area of visceral and subcutaneous fat, and analyze their correlations in a cross-sectional study.We will also analyze the relationship among change of serum VAP-1, obesity, insulin secretion function, and insulin resistance by time in a cohort study (specific aim 2D). In specific aim 2E, we will investigate if serum VAP-1 changes by rosiglitazone in a randomized, placebo-controlled clinical trial in subjects with type 2 diabetes.