Recently, an emerging epidemic of type 2 diabetes in youth has been recognized, primarily (but not exclusively) affecting minority populations. This phenomenon parallels the alarming increase in the prevalence of obesity in children and adolescents. Studies performed in our group over the past 15 years on developmental changes in insulin secretion and action in children and on the metabolic consequences of juvenile obesity, the most common cause of severe insulin resistance in youth have laid the groundwork for the current proposal. We hypothesize that the adverse effects of obesity, puberty and ethnicity may combine to produce such a severe degree of insulin resistance that maximal beta-cell secretion is insufficient to maintain euglycemia. On the other hand, progression to overt diabetes likely requires some degree of beta-cell failure. We further hypothesize that exaggerated insulin resistance in youth at risk for IGT and type 2 diabetes is due, at least in part, to accumulation of visceral and intramyocellular fat (IMCL), as well as an impaired ability to suppress lipolysis in fat and muscle tissue.
The specific aims are: l) to determine the relative role of insulin resistance and beta-cell function in the early stages or the development of type 2 diabetes in youth. We propose to study and follow longitudinally insulin action and secretion in Caucasian and African-American obese adolescents with normal glucose tolerance (NGT) and with impaired glucose tolerance (IGT); 2) to determine whether impaired suppression of lipolysis in subcutaneous adipose tissue and skeletal muscle tissue is linked to the insulin resistance of obese children with NGT, JGT and at the onset of type 2 diabetes; 3) to quantify specifically intramyocellular lipid accumulation in metabolically well characterized children with NGT, IGT and new onset type 2 diabetes. The combination of whole body metabolic methods (glucose clamps, stable isotope kinetic and indirect calorimetry) with state-of-the-art techniques of microdialysis to assess changes in lipolysis in adipose and muscle tissues and the use of 1H-NMR spectroscopy to assess non-invasively IMCL stores, will provide the unique opportunity to advance the understanding of the underlying pathophysiology of type 2 diabetes in youth. The long-term goal is to generate data that will lead to the development of new strategies for the prevention and treatment of type 2 diabetes in youth.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZDK1-GRB-6 (O2))
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Grave, Gilman D
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Yale University
Schools of Medicine
New Haven
United States
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