Childhood Obesity, and its associated metabolic complications, is rapidly emerging as one of the greatest global challenges of the 21st century. This application builds on a long track record of interdisciplinary collaboration among investigators using state of the art insulin clamp, MRS/MRI and stable isotope methodologies for noninvasively assessing muscle glucose metabolism in children. The first cycle of this grant started in 1991, investigating the correlates of Insulin Resistance, the most common metabolic complication of childhood obesity. Using epidemiological and physiological approaches we found that insulin resistance in obese children and adolescents is the best predictor of cardiometabolic risk factors and glucose intolerance and is associated with biomarkers of inflammation. These studies revealed a critical link between insulin resistance and altered tissue lipid partitioning in obese adolescents. The overall and continuing goal of the studies proposed in this competing renewal grant are to elucidate the putative mechanisms of insulin resistance in obese adolescents and to address a novel hypothesis regarding the potential role of Mitochondrial Dysfunction and Impaired Adipogenesis in its pathogenesis.
The specific aims are: 1) to assess whether decreased mitochondrial function, using 31P Magnetic Resonance Spectroscopy (MRS), may contribute to the increased intramyocellular (IMCL) lipid content in obese adolescents;2) to determine whether the obese phenotype characterized by high proportion of visceral fat and a low abdominal superficial layer is associated with an increased proportion of small adipose cells and reduced expression of genes regulating adipocyte proliferation and;3) to determine prospectively whether the obese adolescents with a high proportion of visceral and low subcutaneous fat depots will develop a worsening of glucose tolerance. These hypotheses-driven patient oriented research studies will be performed by a multidisciplinary team of investigators from several departments: Internal Medicine: (Dr Gerald Shulman), Diagnostic Radiology (Drs Constable and Rothman), NIDDK (Dr Sam Cushman), using an integrated team approach.

Public Health Relevance

Childhood Obesity is becoming the most common nutritional disorder worldwide. About 110 million children worldwide are now classified as overweight or obese, particularly African American and Hispanic Youths. Insulin Resistance, the insensitivity of peripheral tissues (e.g. muscle, liver and adipose tissue) to the effects of insulin, is the best predictor of whether the obese child will develop type 2 diabetes. Our previous studies using Magnetic Resonance Spectroscopy (MRS) and imaging (MRI) have clearly established the link between the fat content in the muscle of obese adolescents and insulin resistance. The present studies will focus on determining what might cause fat to accumulate in the muscle and deep abdominal cavity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD028016-18
Application #
8289610
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Grave, Gilman D
Project Start
1991-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
18
Fiscal Year
2012
Total Cost
$261,103
Indirect Cost
$103,337
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Holder, Tara; Giannini, Cosimo; Santoro, Nicola et al. (2014) A low disposition index in adolescent offspring of mothers with gestational diabetes: a risk marker for the development of impaired glucose tolerance in youth. Diabetologia 57:2413-20
Santoro, Nicola; Caprio, Sonia; Giannini, Cosimo et al. (2014) Oxidized fatty acids: A potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents? Antioxid Redox Signal 20:383-9
Giannini, Cosimo; Dalla Man, Chiara; Groop, Leif et al. (2014) Co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes. Diabetes Care 37:475-82
Giannini, Cosimo; Caprio, Sonia (2013) Progression of ýý-cell dysfunction in obese youth. Curr Diab Rep 13:89-95
Kursawe, Romy; Caprio, Sonia; Giannini, Cosimo et al. (2013) Decreased transcription of ChREBP-?/? isoforms in abdominal subcutaneous adipose tissue of obese adolescents with prediabetes or early type 2 diabetes: associations with insulin resistance and hyperglycemia. Diabetes 62:837-44
Giannini, Cosimo; Feldstein, Ariel E; Santoro, Nicola et al. (2013) Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab 98:2993-3000
D'Adamo, Ebe; Santoro, Nicola; Caprio, Sonia (2013) Metabolic syndrome in pediatrics: old concepts revised, new concepts discussed. Curr Probl Pediatr Adolesc Health Care 43:114-23
Kim, Grace; Giannini, Cosimo; Pierpont, Bridget et al. (2013) Longitudinal effects of MRI-measured hepatic steatosis on biomarkers of glucose homeostasis and hepatic apoptosis in obese youth. Diabetes Care 36:130-6
Santoro, Nicola; Feldstein, Ariel E; Enoksson, Erik et al. (2013) The association between hepatic fat content and liver injury in obese children and adolescents: effects of ethnicity, insulin resistance, and common gene variants. Diabetes Care 36:1353-60
Giannini, Cosimo; Weiss, Ram; Cali, Anna et al. (2012) Evidence for early defects in insulin sensitivity and secretion before the onset of glucose dysregulation in obese youths: a longitudinal study. Diabetes 61:606-14

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