Type 2 Diabetes (T2D) 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. This study intends to determine if genetic factors are associated with defects in insulin secretion, the incretin system and hepatic insulin resistance in obese adolescents. The long-term goal of this study is to generate information on both the genetics as well as the pathophysiology of Type 2 Diabetes in Youth, which ultimately might guide the investigators towards better preventive and treatment avenues.
Name: Oral Glucose Tolerance Test
Name: Hyperglycemic Clamp
Name: Isoglycemic Intravenous Glucose Test
Name: Hyperinsulinemic Euglycemic Clamp and 2H20
Description: An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects are pre-IGT or IGTMeasure: Glucose tolerance status Time: Baseline
Description: DNA screening to measure whether subject is CC or TT genotypeMeasure: Genotype Time: Baseline
Description: AIRmax stimulation test during the hyperglycemic clamp to ascertain the maximal acute insulin response (AIR) to arginine, which is a measure of functional beta cell capacity.Measure: Beta cell capacity Time: Baseline
Description: Subjects will undergo the IsoIVGT test with GLP-1 measurements to measure the incretin effectMeasure: Incretin effect Time: 3weeks to 1 month post Baseline testing
Description: The AIRmax stimulation test during the hyperglycemic clamp will be repeated at 2 years to determine if genotype TCF7L2 contributes to worsening in beta cell function longitudinallyMeasure: Beta cell function (longitudinally) Time: 2 years post Baseline
Description: Measurements from the Hyperinsulinemic Euglycemic Clamp/ 2H20 Study will be used to assess insulin effects on hepatic glucose production and glycerol kinetics isotopes and the deuterium enrichment at carbons 2 and 5 (C2 and C5) of plasma glucose providing information on glucose fluxesMeasure: Hepatic glucose fluxes Time: 2 months post baseline testing
There is one SNP
To delineate the effects of TCF7L2 rs7903146 on functional Beta-Cell Capacity in obese adolescents with Impaired Glucose Tolerance (IGT) and pre-IGT.
Aim 2. To examine the functional effect of the rs7903146 variant in the TCF7L2 gene on a) incretin effect in obese adolescents with IGT and pre-IGT.
Aim 3. To determine the functional effects of TCF7L2 rs7903146 SNP on hepatic glucose fluxes in obese adolescents with IGT and pre-IGT.