This proposal seeks NEW support for studying mechanisms contributing to the rapid loss in beta cell function we assembled a large multiethnic cohort of youths (n=1100) and genotyped them together with Dr. Leif Groop for relevant common gene variants known to be associated with T2D in adults from the GWAS. occurring early in the natural history of youth onset T2D. Recently, Although the number of relevant T2D susceptibility genes has been climbing, the rs7903146 SNP in the TCF7L2 gene remains the single strongest known genetic risk factor for T2D. Remarkably, we found in children that each copy of the T allele (rs7903146) is associated with a 1.914 (1.474-2.486) increased adjusted odds for IGT/T2D (p=0.0001), making it one of the most significant genetic findings in T2D to date in youth, with an effect size greater than that reported in adults (18,19,24,26). Additionally, recent preliminary data from our cohort suggest that the TCF7L2 risk genotype is associated with a reduced Disposition Index and a high odds ratio (OR 2.372 95%CI 1.059 - 5.314; p= 0.03) of maintaining IGT or progressing to T2D. Building upon our exciting results we plan to capitalize and utilize our large thoroughly genotyped/phenotyped cohort to test the following Hypothesis: The risk allele at rs7903146 locus favors the maintenance of IGT or its progression to T2D in youth because of a) reduced functional beta cell capacity, b) reduced incretin effect or reduced efficiency of GLP-1 to stimulate insulin secretion and c) increased hepatic insulin resistance.
The Specific Aims are:
Aim 1 a. To delineate the effects of TCF7L2 rs7903146 on functional Beta-Cell Capacity in obese adolescents with IGT.
Aim 1 b. To determine if the risk genotype in TCF7L2 is associated with worsening in beta cell function longitudinally, thereby affecting changes in glucose tolerance. Approach: To assess functional beta cell capacity (mass) we will use clamp-derived glucose-stimulated C- peptide secretion and maximal C-peptide response to Arginine during hyperglycemia (AIRmax) in obese adolescent carriers of the TT and CC TCF7L2 genotype. After a follow-up period of 2 years the OGTT and hyperglycemic?AIRmax tests will be repeated.
Aim 2. To examine the functional effect of the rs7903146 variant in the TCF7L2 gene on a ) incretin effect and b ) on GLP-1-induced insulin secretion in obese adolescents with IGT. Approach: The incretin effect will be measured by AUC of the c-peptide during OGTT and IsoG-IVGTs (29,30). GLP-1 stimulated insulin secretion will be assessed during a hyperglycemic clamp with GLP-1 administration (31).
Aim 3. To determine the functional effects of TCF7L2 rs7903146 SNP on hepatic glucose fluxes in obese adolescents with IGT. Approach: Hepatic glucose production (6-6-D glucose) gluconeogenesis (2H2O technique) will be quantified during a 3 h r hyperinsulinemic-euglycemic clamp using the C5-to-C2 glucose ratio (32-37).
Type 2 Diabetes in obese youth is often preceded by a prediabetic state called: Impaired Glucose Tolerance (IGT), which is associated with a pre-existing defect in insulin secretion. We will determine here if genetic factors are associated with defects in insulin secretion and incretin system and hepatic insulin resistance in obese adolescents. 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.
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|Zabarsky, Gali; Beek, Cherise; Hagman, Emilia et al. (2018) Impact of Severe Obesity on Cardiovascular Risk Factors in Youth. J Pediatr 192:105-114|
|Umano, Giuseppina R; Caprio, Sonia; Di Sessa, Anna et al. (2018) The rs626283 Variant in the MBOAT7 Gene is Associated with Insulin Resistance and Fatty Liver in Caucasian Obese Youth. Am J Gastroenterol 113:376-383|
|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; Caprio, Sonia; Rosaria Umano, Giuseppina et al. (2018) Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort. Hepatology 68:1376-1390|
|Umano, Giuseppina R; Shabanova, Veronika; Pierpont, Bridget et al. (2018) A low visceral fat proportion, independent of total body fat mass, protects obese adolescent girls against fatty liver and glucose dysregulation: a longitudinal study. Int J Obes (Lond) :|
|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|
|Weiss, Ram; Santoro, Nicola; Giannini, Cosimo et al. (2017) Prediabetes in youth - mechanisms and biomarkers. Lancet Child Adolesc Health 1:240-248|
|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|
|Nagarajan, Arvindhan; Petersen, Max C; Nasiri, Ali R et al. (2016) MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nat Commun 7:12639|