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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD040787-01
Application #
6311092
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O2))
Program Officer
Grave, Gilman D
Project Start
2000-09-22
Project End
2005-06-30
Budget Start
2000-09-22
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$367,875
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Galderisi, Alfonso; Giannini, Cosimo; Weiss, Ram et al. (2018) Trajectories of changes in glucose tolerance in a multiethnic cohort of obese youths: an observational prospective analysis. Lancet Child Adolesc Health 2:726-735
Tricò, Domenico; Natali, Andrea; Mari, Andrea et al. (2018) Triglyceride-rich very low-density lipoproteins (VLDL) are independently associated with insulin secretion in a multiethnic cohort of adolescents. Diabetes Obes Metab 20:2905-2910
Tricò, Domenico; Di Sessa, Anna; Caprio, Sonia et al. (2017) Oxidized Derivatives of Linoleic Acid in Pediatric Metabolic Syndrome: Is Their Pathogenic Role Modulated by the Genetic Background and the Gut Microbiota? Antioxid Redox Signal :
Tricò, Domenico; Prinsen, Hetty; Giannini, Cosimo et al. (2017) Elevated ?-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents. J Clin Endocrinol Metab 102:2473-2481
Cropano, Catrina; Santoro, Nicola; Groop, Leif et al. (2017) The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing ?-Cell Function and Hepatic Insulin Sensitivity. Diabetes Care 40:1082-1089
Caprio, Sonia; Perry, Rachel; Kursawe, Romy (2017) Adolescent Obesity and Insulin Resistance: Roles of Ectopic Fat Accumulation and Adipose Inflammation. Gastroenterology 152:1638-1646
Goffredo, Martina; Caprio, Sonia; Feldstein, Ariel E et al. (2016) Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology 63:117-25
Hershkop, Karen; Besor, Omri; Santoro, Nicola et al. (2016) Adipose Insulin Resistance in Obese Adolescents Across the Spectrum of Glucose Tolerance. J Clin Endocrinol Metab 101:2423-31
Kursawe, Romy; Dixit, Vishwa D; Scherer, Philipp E et al. (2016) A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 65:610-8
Zheng, Chao; Dalla Man, Chiara; Cobelli, Claudio et al. (2015) A common variant in the MTNR1b gene is associated with increased risk of impaired fasting glucose (IFG) in youth with obesity. Obesity (Silver Spring) 23:1022-9

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