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.
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.
|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|
|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|
|Van Name, Michelle; Giannini, Cosimo; Santoro, Nicola et al. (2015) Blunted suppression of acyl-ghrelin in response to fructose ingestion in obese adolescents: the role of insulin resistance. Obesity (Silver Spring) 23:653-61|
|Santoro, Nicola; Caprio, Sonia; Pierpont, Bridget et al. (2015) Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene. J Clin Endocrinol Metab 100:E1125-32|
|Weiss, Ram; Magge, Sheela N; Santoro, Nicola et al. (2015) Glucose effectiveness in obese children: relation to degree of obesity and dysglycemia. Diabetes Care 38:689-95|
|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|
|Santoro, Nicola; Caprio, Sonia (2014) Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in obese adolescents: a looming marker of cardiac dysfunction. Hepatology 59:372-4|
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