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.

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.