News & Research

    Yale University, New Haven, Connecticut

Mechanisms of insulin resistance in childhood obesity

General Research Subject: Type 2 Diabetes

Focus: Pediatrics, Pediatrics\Type 2

Type of Grant: Distinguished Clinical Scientist

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Funded by The Amylin Pharmaceuticals Distinguished Clinical Scientist Award

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, b) reduced fat stores in the subcutaneous abdominal layer with  accumulation of  fat in  the visceral compartment, liver and muscle tissues . These youngsters with this particular pattern of fat distribution are extremely insulin resistant and at high risk for Type 2 diabetes. 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) Do obese adolescents with marked insulin resistance have problems localized in their muscle which results in the reduced capacity of the muscle to burn more fat? Is accumulation of fat in the muscle related to impaired oxidative capacity (mitochondrial dysfunction) in obese adolescents?

The studies proposed here will provide further insights in the causes of insulin resistance, a key player in the development of T2DM in Youth and serve as a template for intervention study for the prevention of T2DM in obese youngsters in the community.

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? 

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'. To understand its pathogenesis in youth, in 2000 we began to use the model of 'Impaired Glucose Tolerance' (IGT), an intermediate stage in the natural history of T2DM. The study of impaired glucose tolerance allows us to define the earliest metabolic defects that might lead to the development of overt diabetes.  Understanding the earliest metabolic problems implicated in the development of Type 2 diabetes might lead to more rational 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 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 by preventing the deposition of fat in these sites, like the 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 liver and the risk of diabetes in obese youngsters.   

This Distinguished Clinical Scientist Award from the ADA will allow me to continue this line of work by allowing me to 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 at 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.