News & Research

    Joslin Diabetes Center, Boston, Massachusetts

Molecular Mechanisms of Diabetes Risk

General Research Subject: Type 2 Diabetes

Focus: Obesity\Animal Models

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Low birth weight infants are at increased risk for developing diabetes and obesity (increased body fat) as adults. These risks are even greater in low birth weight infants who undergo a period of rapid growth in the early postnatal period. Studies using a mouse model of low birth weight with rapid postnatal growth indicate that genes involved in vitamin A (or retinol) metabolism are activated within their fat deposits. One of these genes, RBP4, encodes a carrier of vitamin A which has recently been shown to interfere with insulin action in mice, and to correlate with insulin sensitivity in humans. Altered levels of RBP4 may therefore explain why low birth weight individuals are at higher risk for diabetes. To test this, RBP4 levels will be experimentally lowered in low birth weight mice, to see whether this will prevent the development of insulin resistance and diabetes. These studies may lead to the development of treatments to help prevent low birth weight infants from developing type 2 diabetes and other complications.

Reseacher Profile

Mentor: Mary Elizabeth Patti, MD   Postdoctoral Fellow: Alison Burkart, PhD

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

The overall goal of our laboratory investigation is to understand abnormalities present at a cellular level in humans with diabetes risk prior to the development of type 2 diabetes.   We are hopeful that identifying and understanding these patterns will allow us to identify markers of diabetes risk as well as new strategies to treat diabetes.  The ultimate goal would be to apply this to patient care, so that we can intensively target prevention strategies specifically to those individuals at very high risk for type 2 diabetes and cardiovascular disease.

One of the risk factors we are specifically focused on is low birth weight.  Babies with low birth weight, particularly when followed by rapid weight gain in early childhood, are at higher risk for diabetes development.  These findings indicate that diabetes risk begins very early in life, and appears to be related to how nutrition changes how genes are turned on or off during critical periods of growth and development.   Fortunately, there is good news - altering nutrition during early life can normalize risk of diabetes.  We are working to identify the specific dietary changes during early life which can maximally reduce risk.  Ultimately, we hope that this information will translate into trials of dietary modification for low birth weight infants, so as to reduce their ultimate risk for development of obesity and diabetes. 

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

Our studies are designed to understand how risk factors for type 2 diabetes, including early life nutrition and family history of diabetes, affect the function of cells and tissues critical for the body's metabolism and responsiveness to insulin.  In particular, we wish to identify abnormal patterns of metabolism and regulation of how genes are turned on/off which occur prior to the onset of diabetes.  Identification of these patterns and understanding the underlying causes will allow us to develop markers to assess diabetes risk and hopefully to better target specific preventive strategies for individuals at high risk for diabetes. 

As a concrete example, we have recently identified a cellular pathway dysregulated in individuals at risk for diabetes (based on family history).  We are beginning mouse experiments to determine if a drug which can alter activation of this pathway can improve diabetes control in obese mice - stay tuned!

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

Prior to becoming an endocrinologist, I was practicing general internal medicine.  In this setting, I frequently noted the impact of diabetes on many of my patients' health, and became determined to learn more about this disease and to improve the health of those with diabetes. This perspective continues to motivate me in my role as an endocrinologist and scientist - in my goals of working toward understanding the causes of diabetes so we can ultimately devise better treatments and prevention strategies.

This award will allow me to continue to train postdoctoral fellows in diabetes-related research and hopefully to inspire them to commit to prevention and cure of diabetes as well.  The mentor-based research grant support is absolutely critical for our overall research efforts as well since it funds a fellow who may not be eligible for governmental funding (e.g. if not a US citizen) , and also will be key to maintaining lab funding during this difficult period of governmental grant support.

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

There are many important needs in diabetes-related research, ranging from improving clinical care to understanding the basic pathophysiology of diabetes at a molecular level.  An especially critical public health need is to understand why the incidence of diabetes is skyrocketing within the past few decades - and thus to focus particular efforts on environmental contributions to obesity and diabetes.  This is so critical for implementing population-based strategies to prevent diabetes.