McGraw, Timothy E., PhD
Insulin-regulation of the trafficking of the Glut4 glucose transporter
General Research Subject: Type 2 Diabetes
Focus: Adipocytes, Insulin Action, Insulin Action\Glucose Transport, Insulin Action\Insulin Resistance
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
Insulin controls blood glucose levels, in part, by controlling the transport of glucose from the blood into muscle and fat cells. This regulation is defective in type 2 diabetes, contributing to elevated blood glucose of that disease. Insulin regulation of glucose transport is by a complex mechanism that controls the amount of a glucose transporter (known as Glut4) on the surface of cells. The details of this mechanism are not understood.
In this project I propose studies to better understand how insulin regulates the amount of Glut4 on the surface of adipocytes. The long term objective of this work is to identify the proteins required for normal regulation of Glut4, use this information to identify what is defective in type 2 diabetes and thereby identify potential targets for the development of pharmacologic agents that mimics insulin's effects on glucose transport as a treatment for type 2 diabetes.
Mentor: Timothy McGraw, PhD Postdoctoral Fellow: Dorothee Mollee, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
One of the main acute effects of insulin is to stimulate glucose transport into fat and muscle cells by recruiting the GLUT4 glucose transporter from intracellular storage compartments to the surface of cells. At the cell surface GLUT4 acts as a channel allowing glucose to move from outside the cell across the cell membrane into the cell where it can be stored for future energy use. Insulin regulated redistribution of GLUT4 to the cell surface is defective in type 2 diabetes, contributing to elevated blood glucose levels. In my lab we study insulin action at the cellular level. We use isolated adipocytes as a model system, and quantitative fluorescence microscopy methods and cellular molecular biology tools to interrogate insulin action. Dr. Molle’s work will lead to a better understanding of how information from the insulin receptor is transmitted to the GLUT4 glucose transporter. An understanding of how insulin signaling works at a molecular level is required to understand how this signaling is disrupted in insulin resistance and type 2 diabetes mellitus. This knowledge may lead to the identification of targets for therapeutic interventions to prevent or treat insulin resistance that underlies the development of 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?
Work in my lab is designed to understand insulin action at a cellular level. Although these types of basic research studies are a couple of steps removed from translational work targeted toward the development of new regimes for treatment and prevention of type 2 diabetes, the results of basic research provides a foundation and a direction for translational work. The impact of basic research on the prevention and treatment of human diseases is well documented. I hope that our work, by contributing to a more detailed understanding of insulin action, will ultimately impact the prevention and treatment of diabetes. Moreover, this award provides a training opportunity for Dr. Molle, a motivated young scientist interested in a career in diabetes research. The recruitment of talented young scientists to the field of diabetes research is of major importance for the field and therefore this fellowship award, by supporting training, will have long lasting impact on diabetes research.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Obesity and diabetes have a devastating impact on human health. The increased incidence of insulin resistance (and obesity) among young people suggest that type 2 diabetes will be one of the major health issues for decades to come. I believe, based on my particular expertise in basic research, that work from my lab can make a difference in understanding insulin resistance and diabetes. I was not trained as a diabetes researcher but rather joined the field because I felt my work could contribute to a better understanding of insulin action. This award affords me the opportunity to provide training in molecular cell biology and quantitative microscopy methods to fellows committed to careers in diabetes research. I believe studies using these methods will continue to advance our understanding of insulin action at a cellular level and also to contribute to a better understanding of the impact of over-nutrition on insulin action.
In what direction do you see the future of diabetes research going?
I believe future work in the field will include more cell biological studies to advance understanding of insulin action and the effects of over-nutrition on insulin action at a cellular level. Recent technical advances in the study of insulin action in muscle and fat cells using quantitative microscopy methods have led to a number of significant refinements in the models for how insulin recruits GLUT4 to the surface of cells. The results of these basic science studies redefine the questions to be addressed in studies of metabolism at the whole organism level (that is, in studies of genetically altered mice). In addition, in the future I think greater emphasis will be placed on understanding how insulin action is modulated by other hormonal systems. For example, the gut produced incretin hormones that coordinate peripheral insulin-response to the nutrient load sensed by the gut. It is clear that there are a number of ways to modulate insulin-sensitivity of various tissues and it is important to get a better understanding of these mechanism at a molecular level.
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