• DIABETIC SUBJECTS:

INCLUSION CRITERIA:

1. Type 2 diabetes mellitus as defined by:

   1. Fasting blood glucose greater than or equal to 126 mg/dL OR postprandial blood sugar greater than or equal to 200 mg/dL (either during OGTT at NIH or as previously documented on outside medical record)

      Since subjects may already have been started on treatment with hypoglycemic agents at the time of enrollment, they may have blood glucose levels in the impaired glucose tolerance range (fasting glucose 100-125 mg/dL and postprandial 140-199 mg/dL). This is a sign of adequately controlled diabetes, rather than an incorrect diagnosis of diabetes. Therefore, prior documentation (on outside medical records) of blood glucose values documenting diabetes will be acceptable if the subject has impaired glucose tolerance rather than overt diabetes according to screening results at NIH.

   2. Absence of insulin autoantibodies (in insulin naive patients only)
2. Duration of diabetes less than or equal to 2 years (since diagnosis)
3. BMI greater than or equal to 85th percentile for age
4. Age 12-25 years at enrollment

EXCLUSION CRITERIA:

1. Normal OGTT at NIH (fasting blood glucose less than 100 mg/dL AND 2-hour blood glucose less than 140 mg/dL)
2. Monogenic causes of diabetes (e.g. maturity-onset diabetes of the young [MODY] or mitochondrial diabetes). Subjects will be excluded if there is a known personal or family (first degree relative) history of monogenic diabetes. Genetic testing for monogenic causes of diabetes will be performed on potential subjects if the family history is suggestive of monogenic diabetes.
3. Significant comorbidity that, in the opinion of the investigators, will increase risk to the subject, such as coronary artery disease or any heart disease that increases risk associated with exercise (e.g. hypertrophic obstructive cardiomyopathy), renal impairment with serum creatinine greater than 1.4 mg/dL, or current treatment for cancer. Specific obesity-related comorbidities are explicitly permitted, including hypertension, hyperlipidemia, obstructive sleep apnea and non-alcoholic steatohepatitis.
4. Current use of insulin
5. Current use of prescription or non-prescription weight-loss drugs
6. Positive urine pregnancy test or plans to become pregnant during the clinical trial
7. Known allergy, sensitivity or other contraindication to any study drug or its vehicle
8. Psychiatric or cognitive disorder that will, in the opinion of the investigators, limit the subject's ability to comply with study medications and monitoring

MATCHED VOLUNTEERS:

INCLUSION CRITERIA:

Two types of volunteers will be recruited:

1. Age, sex, race and BMI matched with study enrollees who have T2DM
2. Normal weight (BMI between 5th and 85th percentiles for age) volunteers who are age, sex and race matched to subjects with T2DM

EXCLUSION CRITERIA:

1. Diabetes and impaired glucose tolerance
2. Significant comorbidity that, in the opinion of the investigators, will increase risk to the subject (specific obesity-related comorbidities are explicitly permitted, including hypertension, hyperlipidemia, obstructive sleep apnea and non-alcoholic steatohepatitis)
3. Current or recent (past 2 months) use of drugs that alter glucose metabolism (e.g. metformin)
4. Current use of prescription or non-prescription weight-loss drugs
5. Positive urine pregnancy test