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.
The Specific Aims of this study are: Aim 1a. To delineate the effects of TCF7L2 rs7903146 on functional Beta-Cell Capacity in obese adolescents with Impaired Glucose Tolerance (IGT) and pre-IGT. Aim 1b. To determine if the risk genotype in TCF7L2 is associated with worsening in beta cell function longitudinally, thereby affecting changes in glucose tolerance. 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.
Study Type
OBSERVATIONAL
Enrollment
100
The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.
Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.
Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.
Yale University
New Haven, Connecticut, United States
Glucose tolerance status
An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects are pre-IGT or IGT
Time frame: Baseline
Genotype
DNA screening to measure whether subject is CC or TT genotype
Time frame: Baseline
Beta cell capacity
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.
Time frame: Baseline
Incretin effect
Subjects will undergo the IsoIVGT test with GLP-1 measurements to measure the incretin effect
Time frame: 3weeks to 1 month post Baseline testing
Beta cell function (longitudinally)
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 longitudinally
Time frame: 2 years post Baseline
Hepatic glucose fluxes
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 fluxes
Time frame: 2 months post baseline testing
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Test is used to assess insulin effects on hepatic glucose production.