News & Research

    Yale University School of Medicine, New Haven, Connecticut

Cellular mechanisms of insulin resistance in humans.

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Integrated Physiology\Liver, Integrated Physiology\Muscle, Integrated Physiology\Regulation of Glucose Kinetics

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2009

Project End Date: June 30, 2013

Research Description

Type 2 diabetes mellitus (T2DM) is the most common metabolic disease in the world. While the precipitating factors causing this disease are unknown it is clear that insulin resistance has a major role in its development. The primary objective of my lab is to elucidate the molecular mechanism(s) responsible for insulin resistance, which occurs in patients with T2DM, in order to enable the rational development of new therapeutic agents to reverse this pathologic condition as well as assist with identification of candidate genes, which make individuals prone to this disease. Since liver and muscle are the two key insulin responsive organs which account for most of the glucose metabolized in humans, we are currently focusing our attention on these tissues in young prediabetic subjects using magnetic resonance spectroscopy (MRS) in combination with stable isotopes to assess alterations in carbohydrate, fat and protein metabolism in these individuals. This approach has major advantages over existing techniques in that it is noninvasive, it involves no ionizing radiation and repeated measurements of biochemical metabolites in liver, muscle and brain can be performed, which will then yield localized rates of glucose, fat and protein metabolism in humans for the first time. The goal of this ADA Mentor-Based Postdoctoral Fellowship is to provide the support necessary to train the next generation of patient-oriented clinical investigators in the use of these state-of-the art techniques, which will enable them to further elucidate the cellular mechanisms of insulin resistance in patients with T2DM and their insulin resistant offspring.

Reseacher Profile

Mentor: Gerald Shulman, MD, PhD   Postdoctoral Fellow: Tiago Alves, PhD

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

Insulin resistance plays a major role in the pathogenesis of type 2 diabetes mellitus (T2DM) and it is the best predictor for the later development of the disease. The objective of this grant is to elucidate the cellular mechanisms of insulin resistance in liver and skeletal muscle, the two key insulin responsive organs in the body. This grant builds on recent studies from our group in both humans and transgenic/knockout mouse models of T2DM demonstrating a key role of intracellular lipid in the pathogenesis of skeletal muscle and liver insulin resistance. It is anticipated that the results of these studies will yield important new insights into the pathogenesis of insulin resistance and that this information will enable the rational development of novel therapeutic approaches to treat and prevent T2DM.

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

It is anticipated that the results of these studies will yield important new insights into the pathogenesis of insulin resistance in liver and muscle and that this information will enable the rational development of novel therapeutic approaches to treat and prevent T2DM. Furthermore this ADA mentor award will help train the next generation of patient-oriented physician scientists.

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

Type 2 diabetes is reaching epidemic proportions in the USA and it is currently the leading cause of blindness in working adults, the leading cause of end stage renal disease and the leading causes of non-traumatic loss of limb.  Although much progress has been made over the last few decades in our understanding of the pathophysiology of T2DM as a physician taking care of patients with type 2 diabetes I am constantly reminded of the inadequate therapies that are currently available that typically take care of the hyperglycemia but do not get at the underlying root cause of insulin resistance.  This ADA mentor grant will support a postdoctoral research fellow, who will focus on examining the cellular mechanisms of insulin resistance in transgenic and knockout mouse models of insulin resistance.  It is anticipated that the results of these studies will provide new targets for the treatment of T2DM.

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

One of the major factors that promote the development of fasting hyperglycemia and postprandial hyperglycemia in patients with T2DM is non alcoholic fatty liver disease (NAFLD), which is now becoming the most common liver disease in children and adults in the world.  Recent studies by our group have identified important ethnic differences in the incidence of NAFLD and hepatic insulin resistance and we are now trying to identify the responsible genes and respective mechanisms that may be responsible for the increased incidence of NAFLD in these ethnic groups.