News & Research

    Massachusetts General Hospital, Boston, Massachusetts

Refining and expanding the metabolite signature of insulin action under conditions of low and high insulin resistance.

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Genetics\Type 2 Diabetes, Insulin Action\Insulin Resistance, Insulin Action\Metabolism

Type of Grant: ADA-Merck Clinical/Translational Postdoctoral Fellowship

Project Start Date: July 1, 2011

Project End Date: June 30, 2013

Research Description

Insulin resistance (IR) is a central risk factor in the development of type 2 diabetes (T2D), and treatment of IR can prevent T2D. However, the biological mechanisms by which IR ensues and progresses are poorly understood. This study aims to elucidate metabolic pathways that are differentially affected by insulin under states of low and high IR. This study may point to new strategies for identifying individuals at risk for T2D and novel biological targets for treating IR.
 
This study will use the new technology of metabolite profiling to measure changes in circulating metabolites following perturbations of insulin levels. As substrates and products of metabolism, individual metabolites signal alterations in pathways of biological relevance. All subjects will be challenged with a sulfonylurea medication, which raises insulin and lowers glucose; metformin, which lowers insulin and glucose; and an oral glucose tolerance test, which raises glucose and insulin. Using three different methods to alter insulin levels will identify changes that are specific to insulin action and not to the method of perturbation.

First, investigators will examine changes in over 500 metabolites in 60 volunteers and identify metabolites that change specifically in response to insulin. Then, they will compare the changes in insulin-related metabolites between subjects with low and high IR, and identify metabolites that discriminate the two groups beyond other predictive clinical and genetic markers for IR. These discriminating metabolites may serve as early markers for individuals at risk of T2D and highlight new biological targets for the treatment of IR and T2D.

Research Profile

Mentor: Florez, José Carlos, MD, PhD  Postdoctoral Fellow: Walford, Geoffrey

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

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

The goal of our research is to find markers circulating in blood that help us better understand the process of insulin resistance (IR): a central risk factor in the development of type 2 diabetes (T2D). We postulate that identifying these markers, known as metabolites, will benefit both people with and without T2D.

First, metabolite markers will highlight biological pathways that are important for the development of both IR and T2D. With a better understanding of the pathways involved in these states, we and others can begin to define interventions (such as special diets, exercise routines, or medications) that modulate these pathways, preventing or treating T2D in novel ways. 

Second, metabolite markers will help to identify people without diabetes who are at increased risk of developing the disease in the future. People with high levels of these markers could therefore begin preventative measures before T2D and its complications occur.

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

Both Dr. Walford and I are endocrinologists who specialize in helping people manage their diabetes. While there are effective medications currently available to treat diabetes, we see many patients in our office who struggle to control their blood sugar and who suffer from the complications of diabetes. My goal is to continue a career in diabetes research that complements my career as a medical doctor and to participate in the training of future physician-scientists.

This award will play a very important role in these efforts, particularly in the research training of Dr. Walford. First, it will provide Dr. Walford with two years of generous financial support to focus his efforts on research that will lead to a better understanding of biological pathways involved in type 2 diabetes (T2D). This understanding, in turn, will position Dr. Walford for a research career in the development of new preventions and treatments for T2D.  Second, this award will provide funding that will allow Dr. Walford to attend the American Diabetes Association (ADA) Scientific Sessions for the next two years. Attending this meeting will allow him to continue to learn from other investigators who are conducting similar research to his own and to present his research findings at this international conference.

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

There are many important directions for the future of diabetes research. However, all will likely use advancements in technology to better understand the biology underlying pre-diabetic metabolism and diabetes. Advances in metabolite profiling in combination with genomics, will help to parse the heterogeneous causes of type 2 diabetes and promote insights that will lead to novel preventions, treatments, and ultimately, cure of diabetes.