Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- IGT - Impaired Glucose Tolerance
- Sponsor
- Yale University
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- Hepatic glucose fluxes
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Good general health, taking no medication on a chronic basis;
- •Age 12 to 18 yrs, in puberty (girls and boys: Tanner stage II - IV),
- •BMI (BMI \>85th%) indicating obesity,
- •Girls who are menstruating must have a negative pregnancy test during the study and, when possible, be in the follicular phase during infusion study visits (The follicular phase will be identified according to the last menstrual period record and/or according to the oral contraceptive assumption schedule. The investigators will not perform ovulation testing or hormonal assays);
- •Subject must have normal liver and kidney function, amylase and lipase levels.
- •Pre-IGT or IGT
- •TT or CC genotype.
Exclusion Criteria
- •Baseline creatinine \>1.0 mg;
- •Pregnancy;
- •Presence of endocrinopathies (e.g. Cushing syndrome);
- •Cardiac, renal or pulmonary or other chronic illness;
- •Adolescents with psychiatric disorder or with substance abuse history and taking the drugs that affect glucose metabolism, such as any form of steroids, antipsychotics, progesterone preparations, and others.
Outcomes
Primary Outcomes
Hepatic glucose fluxes
Time Frame: 2 months post baseline testing
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
Beta cell function (longitudinally)
Time Frame: 2 years post Baseline
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
Glucose tolerance status
Time Frame: Baseline
An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects are pre-IGT or IGT
Genotype
Time Frame: Baseline
DNA screening to measure whether subject is CC or TT genotype
Incretin effect
Time Frame: 3weeks to 1 month post Baseline testing
Subjects will undergo the IsoIVGT test with GLP-1 measurements to measure the incretin effect
Beta cell capacity
Time Frame: Baseline
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.