Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)

Inclusion Criteria (during Screening and Run-in period):

• Diabetes by ADA criteria (laboratory determinations of fasting glucose ≥ 126 mg/dL, random glucose ≥ 200 mg/dL, or two-hour OGTT glucose ≥ 200 mg/dL) documented and confirmed in medical record. For patients diagnosed with diabetes during screening who have a normal fasting glucose but an elevated two-hour glucose during an OGTT, the HbA1c must be ≥ 6%.
• Duration since diagnosis less than two years by date of randomization.
• BMI ≥ 85th percentile documented at time of diagnosis or at screening.
• Fasting C-peptide at screening (drawn at least one week after treatment for ketosis or acidosis, if applicable) > 0.6 ng/mL.
• Absence of pancreatic autoimmunity (both GAD and ICA512 negative).
• Age 10-17, with randomization prior to 18th birthday.
• Signed informed consent/assent forms for the pre-randomization period.
• A family member or adult closely involved in the daily activities of the child agrees to participate in the child's treatment.
• Fluency in English or Spanish for both child and family member.
• Patient and family able to fully participate in trial protocol in the opinion of the investigator.

Exclusion Criteria (during Screening and Run-in period):

• Participating in another interventional research study protocol in the past 30 days.
• Genetic syndrome or disorder known to affect glucose tolerance other than diabetes.
• Patient on inhaled steroids at dose above 1000 mcg daily Flovent equivalent.
• Patient on a course of oral steroids within the last 60 days or on oral steroids more than 20 days during the past year.
• Patient on medication(s) that are known to affect insulin sensitivity or secretion within the last 30 days.
• Patient on medication(s) that are known to cause weight gain within the last 30 days.
• Patient on any weight-loss medication(s) within the last 30 days.
• Patient on medication(s) known to affect the metabolism of study drug.
• Inability to comprehend the lowest grade level at which lifestyle intervention materials are prepared, for both child and participating family member.
• Females who are pregnant, planning to become pregnant within two years of enrollment, or who admit sexual activity without appropriate contraception.
• Calculated creatinine clearance 2.5 ULN. If any transaminase 1.5-2.5 times ULN, then patient must be appropriately evaluated by PCP (minimum evaluation includes ceruloplasmin level, alpha-1 antitrypsin phenotype, ANA, anti-smooth muscle antibody, anti-LKM antibody, anti-HCV, and anti-HBc total antibody not IgM, iron, and TIBC) and is eligible if all other causes for elevation are ruled out and it is presumed due only to non-alcoholic fatty liver disease (NAFLD).
• Diabetic ketoacidosis (DKA) at any time after diagnosis unless only a single episode of DKA related to a significant medical illness.
• Physical limitations preventing patient from being randomized to the lifestyle intervention.
• Patient plans to leave the geographic area within one calendar year.
• Abnormal reticulocyte count or HbA1c chromatogram at time of screening.
• Admitted use of anabolic steroids within the past 60 days.
• Other significant organ system illness or condition (including psychiatric or developmental disorder) that would prevent participation in the opinion of the investigator.
• Patient participates in a formal weight-loss program.

Inclusion Criteria (post Run-in and Randomization):

• Duration since diagnosis less than 2 years at randomization.
• HbA1c 300 mg/dL or LDL > 190 mg/dL or triglycerides > 800 mg/dL, despite appropriate medical therapy.
• Refractory anemia: hematocrit < 30% or hemoglobin < 10 gm/dL despite appropriate medical therapy.
• Patient on a thiazolidinedione (TZD) within the last 12 weeks.
• Patient on non-study diabetes medications within the past 6 weeks.
• Patient on inhaled steroids at dose above 1000 mcg daily Flovent equivalent.
• Patient on a course of oral steroids within the last 60 days or on or