News & Research

    Yale University School of Medicine, New Haven, Connecticut

Insulin resistance in obese youth with prediabetes

General Research Subject: Type 2 Diabetes

Focus: Adipocytes, Insulin Action\Insulin Resistance, Pediatrics\Type 2

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: January 1, 2010

Project End Date: December 31, 2013

Research Description

Type 2 diabetes has emerged as a new 'pediatric disorder'. Prior to the development of T2DM, Dr. Caprio found that obese youngsters display a) defects in insulin action and secretion b) reduced fat stores in the subcutaneous abdominal layer with accumulation of fat in the visceral compartment, liver and muscle tissues. Obese youths with altered abdominal fat partitioning and fatty liver are a unique model for studying the initial changes relevant to T2DM. She here proposes to address the following questions:

1) What might lead to a reduced ability to store fat in the subcutaneous abdominal? Is the adipose cell from an obese adolescent with a low volume of abdominal subcutaneous layer different in size and in its ability to proliferate when compared to the cell from an obese adolescent with a large abdominal fat layer?

2) Fatty Liver represents an early manifestation of ectopic fat deposition. Does adipocyte size and macrophage infiltration of the abdominal subcutaneous tissue relate to intrahepatic fat accumulation in obese children and adolescents?

3) Does a pre-existing beta-cell dysfunction further exacerbated by a progressive worsening in insulin sensitivity characterize the onset of glucose intolerance in childhood obesity?

Researcher Profile

Mentor: Sonia Caprio, MD   Postdoctoral Fellow: Romy Kursawe, PhD 

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

Type 2 Diabetes is rapidly emerging as one of the greatest global health challenges of the 21st century and has recently become a 'new pediatric disease'. We are therefore studying the metabolic complications of childhood obesity and type 2 diabetes in youth.

Several animal studies demonstrated that inadequate subcutaneous adipose tissue mass leads to ectopic fat storage with its associated metabolic sequelae. Thus, in obesity and T2DM, insulin resistance develops because of alterations in the partitioning of fat between the adipocyte, muscle and liver.

This study allows us to define the earliest metabolic defects in obesity that might lead to the development of diabetes. Understanding the earliest metabolic problems implicated in the development of Type 2 Diabetes might lead to more rationale interventions for the prevention and treatment of diabetes in youth.

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

Not every obese child develops insulin resistance, one of the critical defects leading to diabetes. Identifying the obese at risk for T2DM and, more importantly, understanding why insulin resistance develops, is very important. Our studies have begun to unravel a particular type of obesity that is associated with fatty liver and accumulation of fat in the skeletal muscle and a decreased amount of fat in the abdominal subcutaneous depot. These youngsters with these kinds of fat tissue profiles are at risk for diabetes. The overall goal of my research project is to prevent diabetes be preventing the deposition of fat in liver and muscle.

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

I have been involved in diabetes research since I graduated from Medical School in 1978, in Naples, Italy. Diabetes is a very difficult metabolic disorder that involves every system in the body. It is hard to control, particularly in children. Lately, with the increasing prevalence of obesity we have seen an unprecedented emergence in the prevalence of T2DM in obese adolescents. My research has clearly indicated that alterations in both insulin action and secretion are present very early - before the onset of the full blown disorder. Moreover, there seems to be a strong association between the amount of fat deposited in the livr and the risk of diabetes in obese youngsters.

The Mentor Award from the ADA will allow me to continue this line of work by allowing me to mentor Romy Kursawe, who will perform more studies, aimed at looking at the mechanisms leading to fatty liver and reduced deposition of fat in the subcutaneous depot of obese adolescents.

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

There is a great need for a better understanding of the underlying pathophysiology of this very complex disease. Importantly, there is need for more studies aimed of understanding the impact of potential environmental factors on the genes involved in both forms of diabetes. Much work needs to be done on the prevention of diabetes.