This proposal requests renewed funding to continue our productive investigations on the Pathophysiology of Type 2 Diabetes in Youth. During the previous cycle we studied the role of insulin resistance and beta-cell secretion in the earliest stage of T2DM, namely: Impaired Glucose Tolerance (IGT). Recent studies by our group have established a strong relationship between fatty liver, prediabetes and T2DM in obese adolescents. Of note, our group has described the longitudinal trajectories in both insulin resistance, beta-cell function and Disposition Index during the transition from NGT to IGT, over a 3 year period in obese adolescents. We found that those who progressed to IGT already had pre-existing defects in beta-cell glucose responsivity at baseline (by the Oral Minimal Model). This series of studies led to our central hypothesis that prior to the onset of IGT or T2DM in youth, inherent genetic variants might be linked to beta-cell dysfunction which will worsen over a relatively short period of time due to the worsening of insulin resistance secondary to the accumulation of lipids in muscle and liver (NAFLD/NASH). Accordingly, we propose to search for genetic determinants of beta-cell defects that we have identified, using detailed phenotyping combined with genotyping of polymorphisms (SNPs) related to beta-cell function. To accomplish this goal we have created an interdisciplinary team of world-renowned scientists at Yale, and in Europe, spanning the breadth from Clinical science (Pediatrics, Epidemiology) and Basic science (Genetics, Bioinformatics).
The specific aims are:
Aim 1 : A) To examine the relationships between a panel of 16 gene variants (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, HHEX, CDC123/CAMK1D, WFS1, TSPAN8/LGR5, THADA, ADAMTS9) and measures of beta-cell function in obese adolescents with a wide distribution of the DI, using the Oral Minimal Model. B) To longitudinally test the individual and cumulative effects of diabetes risks alleles on measures of beta-cell function in non- diabetic obese adolescents across the spectrum of DI, using the Oral Minimal Model.
Aim 2 : A) To determine longitudinally whether adiponectin (total and/or HMW) is associated with hepatic fat accumulation determined by Fast-MRI. B) To determine if circulating adiponectin levels, total and/or the HMW form, distinguish simple hepatic steatosis from steatohepatitis (NASH), and whether it might act as a biomarker of NASH, determined by biopsy. Ultimately, the results of this project will be crucial in attaining our long term goals of (a) understanding the fundamental causes(s) of T2DM in youth and (b) developing strategies to predict and prevent the disease and its complications.

Public Health Relevance

Type 2 Diabetes in obese youth is often preceded by a prediabetic state called: Impaired Glucose Tolerance (IGT) and hepatic steatosis. Importantly, obese adolescents with IGT have pre-existing defect in insulin secretion. We will determine here if genetic factors are associated with defects in insulin secretion in a large cohort of obese children and adolescents and assess if the simple measure of circulating adiponectin may function as a biomarker of hepatic fat accumulation. Our long term goal is to generate information on both the genetics as well as the pathophysiology of Type 2 Diabetes in Youth, which ultimately might guide us towards better preventive and treatment avenues.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD040787-13
Application #
8294732
Study Section
Special Emphasis Panel (ZRG1-EMNR-B (02))
Program Officer
Winer, Karen
Project Start
2000-09-22
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$366,010
Indirect Cost
$144,856
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Santoro, Nicola; Caprio, Sonia (2014) Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in obese adolescents: a looming marker of cardiac dysfunction. Hepatology 59:372-4
Tuomi, Tiinamaija; Santoro, Nicola; Caprio, Sonia et al. (2014) The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383:1084-94
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
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
Savoye, Mary; Caprio, Sonia; Dziura, James et al. (2014) Reversal of early abnormalities in glucose metabolism in obese youth: results of an intensive lifestyle randomized controlled trial. Diabetes Care 37:317-24
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; 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

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