News & Research

    Duke University, Durham, North Carolina

Mitochondrial stress and insulin resistance in skeletal muscle

General Research Subject: Type 2 Diabetes

Focus: Insulin Action\Insulin Resistance

Type of Grant: Career Development

Project Start Date: July 1, 2007

Project End Date: June 30, 2012

Research Description

In recent years the prevalence of metabolic diseases such as obesity and diabetes has increased at epidemic rates. These disease states are closely associated with caloric over-consumption and physical inactivity. Mitochondria are small organelles that function as the powerhouse of most cell types. They adapt to changes in energy supply (diet) and demand (exercise) and play a key role in regulating energy balance. Ongoing studies in our laboratory suggest that the development of obesity and diabetes may be linked to impairments in skeletal muscle mitochondrial function.

Our work provides evidence that a chronic high fat diet imposes a heavy energy burden on muscle mitochondria, which in turn disrupts the muscle?s ability to respond appropriately to insulin, a hormone that controls blood sugar levels. Our application proposes to test the hypothesis that 'stressed' mitochondria produce a metabolic signal that impedes insulin action, thus contributing to the progression of type 2 diabetes. We seek to identify the specific stress-related signals and metabolic events that connect mitochondrial malfunction to diabetes, and to understand the mechanisms by which exercise promotes mitochondrial health and protects against disease.

Reseacher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? 

This project studies the biochemical mechanisms that lead to the development of insulin resistance, a hallmark feature of Type 2 diabetes mellitus. Over 80% of those affected with type 2 diabetes are overweight, indicating that obesity is a strong risk factor for the disease.

The goal of this project is to understand how obesity (a condition of increased body fat) apparently causes IR. We believe that obesity results in increased fat delivery to the muscle, and that fat-derived metabolites interfere with insulin's function. In recent research we have discovered a metabolite that might be an important culprit of fat-induced insulin resistance, and we have proposed new studies to evaluate this metabolite more closely. Results from this research may provide evidence demonstrating a direct cause and effect relationship between production of this metabolite and the onset of insulin resistance. This could in turn lead to the development of novel drugs and/or new dietary interventions that will prevent/treat diabetes by inhibiting the synthesis or accumulation of this specific metabolite.

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

This project could provide novel insights into why/how obesity often results in the development of type 2 diabetes. Such research can pave the way for the design of new drugs and/or dietary strategies aimed at preventing or treating the disease.

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

Because I hold such a strong personal commitment to health and physical fitness, I chose to pursue a research career focused on studying nutritional biochemistry and exercise physiology. Since beginning my scientific career I have witnessed a steady decline in the health status of our population, both nationally and internationally, with obesity and type 2 diabetes being at the forefront this health crisis. Most alarming, is the increasing prevalences of these diseases in children, as well as the burden that these diseases impose on our nation's healthcare system. For these reasons I believe that it is crucial that we advance our scientific understanding of both the genetic and behavioral factors that are contributing to the 'obesity/diabetes epidemic'.

Thus, my long-term career goal is to establish myself an independent academic scientist this field. Obtaining the ADA Junior Faculty Award will allow me to fulfill my career goals by training under the mentorship of Dr. Chris Newgard, current Director of the Sarah W. Stedman Nutrition and Metabolism Center at Duke University. Dr. Newgard is one of the premier diabetes researchers in the nation. The goal of this training will be to expand my technical skills to include those that will enable me to use state-of-the-art molecular strategies to manipulate and analyze muscle metabolic pathways, in cell culture systems, animals models and in human tissues. I view these as an essential set of skills that will greatly enhance my ability to perform the highest quality research in the diabetes field.

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

I envision greater emphasis on multidisciplinary approaches that combine integrative physiology and metabolism with cellular and molecular biochemistry. Additionally, progress towards understanding the cause of diabetes will surely involve application of new technologies that allow more comprehensive and unbiased analysis of the transition between healthy and diseased states. My research plan is based on a conceptual framework that integrates nutritional genomics and metabolomics, molecular physiology and genetic engineering to study mechanisms that cause insulin resistance. New genomic technologies now allow studies that comprehensively evaluate how changes in gene regulation contribute to metabolic diseases. Combining these types of analysis with 'metabolomic' technology (the analysis of large sets of metabolites) offers the ability to evaluate global effects of nutritional/physiological/genetic stresses on gene regulation and simultaneously changes in related metabolites.

By generating new information regarding nutrient-gene interactions, new biomarkers of disease and/or new candidate mediators of disease, this approach can be used to aid in the diagnosis of pre-diabetes and to identify new metabolic targets for dietary and/or pharmaceutical interventions. The functional impact of specifically manipulating a candidate gene and/or metabolite can then accomplished through recombinant DNA technology that allows delivery of a target gene to specialized cells, such as muscle or liver cells, followed by experiments that evaluate consequent changes in metabolic control.