Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes
Condition: IGT - Impaired Glucose Tolerance; T2D
MeSH terms: Prediabetic State; Glucose Intolerance
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Oral Glucose Tolerance Test; Hyperglycemic Clamp; Isoglycemic Intravenous Glucose Test; Hyperinsulinemic Euglycemic Clamp and 2H20
Intervention type(s): Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test
Intervention description(s): 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.; Test is used to assess insulin effects on hepatic glucose production.
Other intervention name(s): OGTT; Infusion Study; IsoG IVGT; E Clamp with labeled water
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects will be selected from the Yale Pediatric Obesity Clinic or from the existing
        cohort of subjects who have had Oral Glucose Tolerance Tests and genotyping. Subjects will
        be Pre IGT and IGT adolescents 12-18 years old with either the CC or TT genotype. 50 CC pre
        IGT/IGT obese patients and 50 TT pre IGT/IGT obese patients will be rectruited.
      
Biospecimen description: 
      DNA will be extracted from whole blood with the use of a Flexigene Kit (Qiagen) and
      genotyping will be performed using a matrix assisted based laser desorption-ionization time
      of flight mass spectrometry on the MassARRAY platform (Sequenom). DNA sample is obtained with
      fasting samples during the OGTT.