News & Research

    University of Washington, Seattle, Washington

The entry of glucose into mammalian cells: structure and function of human glucose transporters

General Research Subject: Type 2 Diabetes

Focus: Insulin Action\Glucose Transport, Integrated Physiology\Regulation of Food Intake, Other

Type of Grant: Career Development

Project Start Date: January 1, 2009

Project End Date: December 31, 2013

Research Description

Glucose is the primary source of energy for all mammalian cells and one of the most difficult challenges faced by type-2 diabetes patients is the control of blood glucose levels. Glucose enters and exits cells through specialized gateways called 'glucose-transporters'. These proteins are abundant and important for life and many diseases are the direct result of mutation or malfunction in glucose-transporters. Of particular interest to the American Diabetes Association, misregulation of glucose transporters result in glucose malabsorption in intestines, an inability to control circulating glucose levels and hyper- or hypo-glycemia.

The precise mechanism by which glucose-transporters bind and transport glucose is poorly understood because the structure of human glucose-transporters is unknown. What is known is that there are at least three general mechanisms by which these gateways function: 1, passively let glucose into cells; 2, use electrical gradients to push glucose through the gateway; and 3, use salt gradients to transport glucose.

We propose to determine the structure for a representative member of each of these three mechanisms of glucose transport. We aim at determining these structures to the highest possible resolution, where the positions of individual atoms can be seen with great accuracy and the mechanism of glucose transport in humans can be unambiguously understood. With this information one could begin to think of innovative and non-invasive ways to control glucose levels in patients simply by modulating the rates at which glucose-transporters function to both block glucose absorption in the intestines and increase glucose secretion into the urine.

Reseacher Profile

What area of diabetes research does your project cover?  

Type-2 diabetes research; Insulin Action-Glucose Transport; Regulation of Food Intake; Protein structure and function.

What role will this particular project play in preventing, treating and/or curing diabetes? 

Elevation of blood glucose is the main symptom in diabetes; a disease reaching epidemic proportions in the United States, affecting 7% of the population and is the sixth leading cause of death (NIDDK statistics). Dietary glucose enters and exits cells through specialized gateways called 'glucose-transporters'. Glucose transporter expression is altered, or signaling cascades interrupted in diabetic patients affecting the ability to regulate blood glucose levels. Glucose transporters are ubiquitous and many diseases including heart disease, hypo- and hyperglycemia and blindness are directly connected with glucose transporters. Glucose, and possibly fructose are the only substrates available for energy production so not surprisingly, glucose transporters are typically misregulated in diseased patients/cells.

No structure for any human glucose transporter has been determined to date but because of the critical role glucose transporters play in regulating blood glucose levels, controlling the function of these transporters has great therapeutic potential in combating life-threatening disease and advancing human health. Therefore glucose transporters are potential drug targets but structural information is needed for the design of effective pharmaceuticals. Our studies will provide this structural information, setting the stage to the innovative design of allosteric ligands aimed at modulating sugar uptake by affecting the active and inactive states of these transporters. Our results will therefore facilitate the development of new approaches to control blood sugar levels and for the prevention, diagnosis and treatment of diverse medical conditions.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

Glucose is the primary source of energy for all mammalian cells and one of the most difficult challenges faced by type-2 diabetes patients is the control of blood glucose levels. Glucose enters and exits cells through specialized gateways called 'glucose-transporters'. These proteins are abundant and important for life and many diseases are the direct result of mutation or malfunction in glucose transporters. Of particular interest to diabetic patients, misregulation of glucose transporters result in glucose malabsorption in intestines, an inability to control circulating glucose levels and hyper- or hypo-glycemia.

The precise mechanism by which glucose-transporters bind and transport glucose is poorly understood because the structure of human glucose-transporters is unknown. We propose to determine the structure of human glucose transporters. We aim at determining these structures to the highest possible resolution, where the positions of individual atoms can be seen with great accuracy and the mechanism of glucose transport in humans can be unambiguously understood. With this information one could begin to think of innovative and non-invasive ways to control glucose levels in patients simply by modulating the rates at which glucose-transporters function to both block glucose absorption in the intestines and increase glucose secretion into the urine.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts? 

My family has been affected by type-2 diabetes. For my doctorate studies therefore, it was important for me to seek laboratories that focus on diabetic research. I joined the laboratory of Professor Joerg Kistler in New Zealand who studies the onset of diabetic cataracts in humans. Quickly it became apparent to me that membrane proteins play a critical role in diabetes and therefore I concentrated my efforts on the structure and function of membrane proteins.

As a postdoctoral fellow at Harvard Medical School I studied the structure and function of the water channel aquaporin-0. This membrane protein is expressed in the eye lens and when mutated it cases severe developmental lesions and cataracts. My studies showed that the protein structural integrity is necessary for maintaining the lens tissue architecture and help explain why mutations in the protein lead to cataracts and blindness.

As an assistant professor at the University of Washington in Seattle, it was important for me to carry on with diabetic research but this time I chose to focus on human glucose transporters. These membrane proteins form the gateway through which dietary glucose enters and exits cells. The structure of glucose transporters is unknown, and therefore their function is poorly understood. My laboratory aims to determine the structure of human glucose transporters, and to provide this information to the scientific and pharmaceutical communities. With this information at hand, new drugs could be designed aimed at changing the rate at which glucose transporters function. In this way, diabetic patients will be given new and non-invasive ways of directly controlling circulating blood glucose levels.

This Career Development Award from the American Diabetes Association will guarantee that my work on human glucose transporters continues.

In what direction do you see the future of diabetes research going? 

Type 2 diabetic patients need to better regulate their blood glucose levels and control the rate at which glucose is absorbed in their intestines. The key question is how can one design new ways of controlling glucose levels in patients? I would argue that glucose levels can be controlled by changing the rate at which glucose transporters function since these transporters form the gateway for glucose absorption. Without functional glucose transporters, very little dietary glucose is absorbed and entire metabolic pathways malfunction.

A major focus of diabetic research therefore must be the structure and function of glucose transporters. Structures can show us exactly where and how glucose binds to the transporter and how glucose is then brought into cells. With the structures of all key transporters at hand, many new avenues for medical research and drug design by the pharmaceutical industry can begin. The ultimate aim will be for devising new and non-invasive ways of controlling glucose levels in diabetic patients by directly modulating the function of glucose transporters. For example, inhibitors that specifically target glucose transporters could be used to control blood glucose levels in diabetic patients by blocking glucose absorption in the intestines and increasing glucose excretion into the urine.