Jiang, Zhen Yue
Novel protein PPC2D functions as a converging point for GLUT4 translocation
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Adipocytes, Insulin Action\Glucose Transport, Insulin Action\Signal Transduction
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Insulin regulation of blood glucose levels is mediated partially through its effect to increase the movement of glucose transporter GLUT4 to the surface of fat and muscle cells and therefore, glucose uptake by these cells. Studies have suggested that enzymes, Akt2 and CaMKII can modify the functions of their target proteins, are activated by insulin and involved in glucose transport. The identification and characterization of downstream signaling molecules linking the kinase pathways to GLUT4 is the most important question in the field of insulin signaling to glucose transport. We have applied a powerful proteomic approach to identify new kinase targets in cultured cells. An unknown protein PPC2D is identified and required for insulin-stimulated glucose uptake and GLUT4 relocation to the surface of fat cells, suggesting that this novel protein is most likely a mediator of insulin-induced glucose metabolism. In this project, we propose to explore the mechanism by which PPC2D regulates GLUT4 relocation to the cell surface in cultured cells, using proteomic and live cell-imaging approaches. Since this novel protein level is significantly reduced in obese mice, we will also examine how PPC2D is activated in the tissues from lean and obese insulin resistant animal models. Hopefully, this project will lead to uncovering a novel signal pathway linking Akt2 and CaMKII activation to glucose transport, and provide potential therapeutic targets for diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The major function of insulin in our body is to regulate glucose (sugar) utilization by mobilizing glucose transporter GLUT4 from inside to the surface of the cells. This project is aimed at understanding the mechanism by which insulin regulates sugar utilization in our cells. We identified a new protein PPC2D that is required for insulin-regulated glucose transport and GLUT4 movement from inside to the surface of the cells. This project is designed to determine how PPC2D is involved in the regulation of glucose transport and GLUT4 movement in fat and muscle cells. This study could provide important information how glucose metabolism is regulated by insulin. Since PPC2D is a protein highly regulated in obesity, it might be a potential therapeutic target for diabetes and its complications.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
It is well established that insulin is the most important hormone in our body regulating blood sugar (glucose) levels by stimulating glucose transport into the fat and muscle cells for metabolism. Blood glucose levels are elevated in both type I diabetes (insulin deficiency) and type II diabetes (insulin resistance), due to lack of insulin’s action in the human body. The elevation of blood sugar is a major factor contributing to the development of diabetes-associated complications. The goal of this project is to understand how insulin regulates glucose transport and utilization. In particular, we are studying the role of a new protein molecule PPC2D in insulin-regulated glucose transport. Insights from these studies may help us to identify potential steps and new molecules involved in the regulation of glucose utilization. Therefore, the outcome of this project might help to identify new drug target(s) for intervening glucose transport and treatment of diabetes and its complications.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is one of the most serious health problems affecting more than 171 million people in 2008 worldwide and this is expected to increase to 366 million by 2030. I have been involved in diabetes-related research for more than a decade. It is my passion to understand how insulin regulates glucose transport and utilization. Previously, we confirmed that insulin signaling pathway via protein kinase Akt2 is important for glucose transport. With the support of a Junior Faculty Award from the American Diabetes Association, I applied quantitative proteomic and functional screening approaches to identify an isoform of C2 domain-containing phosphoprotein PPC2D that is required for insulin-stimulated glucose transport and GLUT4 translocation. This new basic research award from the American Diabetes Association will enable my lab to further study how PPC2D regulates GLUT4 in adipocytes and muscle cells.
In what direction do you see the future of diabetes research going?
I believe that studies related to identifying causative factors of insulin resistance in obesity and basic research on how insulin signaling regulates glucose metabolism are both important for diabetes research. The basic research will include fundamental understanding of molecules involved in and cellular processes of GLUT4 movement. My current project is related to in this area. Applications of advanced techniques, such as quantitative proteomics, lipidomics, genomics, and quantitative microscopy methods, will also help fundamental discoveries in diabetes-related research. These areas of research are critical for the discovery of new therapeutic targets and drugs for diabetes. As we continue to gain insights into the molecular mechanism by which insulin stimulates glucose transport and metabolism, we are identifying potential intervene approaches to improve glucose utilization and therefore, new methods for the treatment of diabetes and its complications.
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