Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

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.

• Oral Glucose Tolerance Test (Diagnostic test), also known as OGTT: 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.
• Hyperglycemic Clamp (Diagnostic test), also known as Infusion Study: Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.
• Isoglycemic Intravenous Glucose Test (Diagnostic test), also known as IsoG IVGT: Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.
• Hyperinsulinemic Euglycemic Clamp and 2H20 (Diagnostic test), also known as E Clamp with labeled water: Test is used to assess insulin effects on hepatic glucose production.

Primary outcomes

• Glucose tolerance status [Baseline]: An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects are pre-IGT or IGT
• Genotype [Baseline]: DNA screening to measure whether subject is CC or TT genotype
• Beta cell capacity [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.
• Incretin effect [3weeks to 1 month post Baseline testing]: Subjects will undergo the IsoIVGT test with GLP-1 measurements to measure the incretin effect
• Beta cell function (longitudinally) [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
• Hepatic glucose fluxes [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

Sex: All, ages: 12 Years to 18 Years

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.

• Sonia Caprio, MD, Principal investigator, Yale University

NIH grants: R01DK111038