Mastick, Cynthia Corley, PhD
Regulation of Glut4 trafficking kinetics by insulin
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Insulin Action
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research focuses on understanding how insulin regulates glucose transport and glucose metabolism in muscle and adipose tissue (fat). Regulation of blood glucose levels is a primary function of insulin, and defects in insulin signaling in these target tissues leads to elevated blood glucose. This elevation in blood glucose is a major contributor to the complications caused by diabetes. Glucose transport in muscle and adipose tissue is controlled by regulating the total number of glucose transport proteins (or Gluts) expressed at the surface of these cells. The Gluts allow glucose to cross the cell's outer membrane and be stored as glycogen and fat inside the cells of these tissues. In the absence of insulin, few Gluts are present at the cell surface, and glucose transport is low. In response to insulin, the Gluts are moved to the cell surface, increasing glucose uptake in the tissues, and removing glucose from the blood. The primary goal of the research in my lab is to understand at the molecular level how the Gluts are moved between intracellular stores and the cell surface. We are particularly interested in understand the biochemical reactions that control this movement in response to insulin. We are also interested in developing assays that will allow all researchers in the field to more easily study this problem. If we understand how glucose transport is regulated in muscle and fat, it is possible that we can identify novel therapeutic targets and develop novel therapies to help diabetic patients regulate their blood glucose levels.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our major goal is to identify how insulin works at the molecular level. If we understand this, then we will understand what goes wrong with insulin signaling in type II diabetes. We believe that this knowledge will lead to new targets for drug discovery and novel points of intervention for the treatment of both type I and type II diabetes. If we understand what happens biochemically when insulin binds to its target tissues, we can potentially bypass the step that is defective in type II diabetes (or the need for insulin in type I diabetes) and stimulate glucose removal directly. These novel therapies will expand the options available to patients to help reach their optimal level of blood glucose control.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Three out of four of my grandparents died from complications from type II diabetes. As a young adult I watched the progression of their disease and wanted to help. I recognized in graduate school that the research approach I was using could be applied directly to the problem of regulation of glucose transport by insulin. I then moved onto postdoctoral training in this area, and continue this research today. Now my mother, my father, and numerous aunts and uncles have been diagnosed with this disease, further strengthening my interest in this area of research. I find it personally very satisfying to be able to relate my own research to such a significant health issue, and to be part of a greater community of researchers who are attacking this problem from many different angles: from molecular biology to lifestyle interventions. Additionally, anything we learn about the molecular mechanisms of insulin action has the potential to directly impact treatment of this disease. It is a very exciting time to be involved in diabetes research. This Research Award comes at a critical time for my lab. I have recently shifted our research focus back to the regulation of glucose transport by insulin. To do this I made the decision to not renew my current NIH grant, which I felt was leading me away from this area of research. This award from the ADA will support our efforts during the transition to a new R01 award.
In what direction do you see the future of diabetes research going?
It is clear from the genetics studies in type II diabetes that the susceptibility to pancreatic failure accounts for a significant amount of the total genetic load that leads to the development of type II diabetes. However, as is so well demonstrated by the progression of gestational diabetes, it is insulin resistance caused by environmental factors (pregnancy, obesity, others not yet identified) that stresses the pancreas into failure. Type I diabetes is also a multi-factorial disorder, with as yet largely unidentified environmental triggers causing an autoimmune response that destroys the pancreas in genetically susceptible individuals. Recent research has focused significantly on the development of novel treatments such as islet transplants, which are at the cutting edge for patient treatment at this time. These areas of research are of great importance, as they affect the lives of diabetic patients today. Much recent research has also focused on the identification of the genetic variations that underlie the susceptibility to diabetes. Identification of these genetic variants will not only lead to a much better understanding of the pathogenesis of the disease, but will also allow the identification of individuals at risk of developing diabetes (although as the NIH director Dr. Francis Collins points out, a good, detailed family history can also very effectively identify at risk individuals). Despite these great advances in the treatment of diabetes, I believe that it is the identification of the environmental factors and development of strategies to prevent these factors from triggering the onset of diabetes that will prove to be the most valuable tool for combating this disease. I believe that the prevention of the onset of disease in the first place (whether it is diabetes or any other disease) is the future direction of all medicine. In order to do this we need a fundamental understanding of the basic biochemistry and physiology of insulin action and glucose metabolism.
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