Please select the eligibility criteria that correspond to the clinical trial below.
Title: Reduction of Adolescent Risk Factors for Type 2 Diabetes and Cardiovascular Disease
Brief Summary: The purpose of this study is to assess the sustainability of a two-year intervention aimed at improving body mass index (BMI) and metabolic and vascular health in obese youth. The study will compare lifestyle changes with diet and exercise alone with changes in lifestyle in combination with metformin medication. An initial intensive exercise program will also be compared with a standard exercise program.

Hypothesis: Metformin therapy in combination with intensive lifestyle intervention in obese children and adolescents will be associated with reduced rate of weight gain, improved BMI, body composition, physical activity, physical fitness, insulin sensitivity, blood lipid profiles, adipocytokines and vascular function.


Options:
A: 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 \< 70 mL/min.
* Any transaminase \> 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 \< 8% on metformin alone.
* Age 10-17, with randomization before patient is 18 years old.
* Signed consent/assent forms for randomization and the post-randomization phase.
* 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 (post Run-in and Randomization):

* Refractory hypertension: average systolic blood pressure ≥ 150 mmHg or average diastolic blood pressure ≥ 95 mmHg despite appropriate medical therapy.
* Refractory hyperlipidemia: total cholesterol \> 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 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, assessed by mastery of standard diabetes education program administered during run-in.
* Inability to comply with requirements of study during run-in period.
* Females who are pregnant, planning to become pregnant within two years of enrollment, or who admit sexual activity without appropriate contraception.
* Calculated creatinine clearance \< 70 mL/min.
* Physical limitations preventing patient from being randomized to the lifestyle intervention.
* Patient plans to leave the geographic area within one calendar year.
* Admitted use of anabolic steroids within 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.
* Episode of DKA during the run-in.30.
* Edema at the time of randomization (a participant who experiences edema during run-in must have recovered within 2 weeks and be edema free for 1 week prior to randomization).
B: * INCLUSION CRITERIA:

Volunteers will qualify if they meet the following criteria:

* Good general health. A normal history and physical examination with the exception of overweight will be required.
* Age greater than or equal to 12 and \< 18 years at the start of the study.
* Female.
* Body mass index measured at the NIH is within the 75th 97th percentile for age, gender, and race.
* English speaking.
* Ability to complete study procedures including the ability to participate in a group.

Individuals will be individually assessed to determine their suitability for group treatment. School placement (e.g. special education) will be used as an estimate of cognitive functioning.

- As assessed by the Eating Disorder Examination structured clinical interview (see methods), a history of LOC eating (objective or subjective bulimic episodes, or both) or no reports of LOC eating.

EXCLUSION CRITERIA:

Volunteers will be excluded (and referred to non-experimental treatment programs as needed) for the following reasons:

* Presence of major illnesses: renal, hepatic, gastrointestinal, most endocrinologic (e.g., Cushing syndrome, hyper- or hypothyroidism), hematological problems or pulmonary disorders (other than asthma not requiring continuous medication). Nonserious medical illnesses, such as seasonal allergies, will be reviewed on a case-bycase basis.
* Presence of an obesity-related medical complication that would require a more aggressive weight loss intervention approach. Such comorbidities include hyperlipidemia (LDL-cholesterol \> 130 mg/dL), hypertension (defined by age- sexand height- specific standards (115) fasting hyperglycemia (fasting glucose \> 126 mg/dL) and nonalcoholic steatohepatitis (ALT above NIH Clinical Center laboratory norms with consistent radiologic findings and absence of another cause such as infectious hepatitis).
* Regular use of prescription medications. Oral contraceptive use will be permitted, provided the contraceptive has been used for at least two months before starting study medication. Individuals taking medications for most conditions will be excluded, but medication use for non-serious conditions (e.g., acne) will be considered on a caseby- case basis. In particular, participants currently prescribed SSRI s, neuroleptics, tricyclics, stimulants, or any medication known to affect body weight or eating will be excluded.
* Current involvement in psychotherapy or a structured weight loss program,
* Weight loss during the past 2 months for any reason exceeding 3% of body weight.
* Pregnant or recently pregnant girls (within 1 year of delivery).
* History of an eating disorder or a current eating disorder (other than binge eating disorder) as determined by medical history or if uncovered during the study s structured clinical interviews. Subjects found to have an eating disorder other than binge eating disorder at baseline will be referred to mental health specialists for further evaluation and treatment.
* Current pregnancy or breast feeding. A negative pregnancy test before starting the study will be required. Because pregnancy is a state in which weight gain is expected and appropriate, pregnant individuals would not be suitable for this study. Sexually active females must be using an effective form of birth control. These methods include total abstinence (no sex), oral contraceptives ( the pill ), an intrauterine device (IUD), levonogestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended.
* Individuals who have DSM-IV-TR major depressive disorder, psychoses, current substance or alcohol abuse, conduct disorder, or a diagnosed psychiatric disorder that, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study. Individuals whose parents or guardians have current substance abuse or a diagnosed psychiatric disorder or other condition that, in the opinion of the investigators, would impede adherence with the study

Each participant will receive a written explanation of the purposes, procedures, and potential hazards of the study. Communication of this information and of the participant s assent, as well as the consent of the parent or guardian, will be documented in the medical record. All participants will be informed of their right to withdraw from the study.
C: Inclusion Criteria:

* Obese adolescents defined as BMI greater than the 95th percentile for age and gender
* Metformin naive subjects

Exclusion Criteria:

* Elevated fasting plasma glucose ≥ 6.0 mmol/L
* 2 hour plasma glucose ≥ 11.1 mmol/L after a standard glucose load
* A1C \> 6.0%
* Medication other than "over the counter" drugs, oral contraceptive pill or thyroid hormone replacement
* Smoking
* Pregnancy
* Renal insufficiency (serum creatinine \> the upper limit of normal)
* Hepatic dysfunction (\> 1.5 times the upper limit of normal for AST and ALT)
* Latex Allergy
* Hypersensitivity to metformin or its ingredients
* Breast feeding
* Subjects with a history of lactic acidosis
* Abnormal creatinine clearance
* HIV, HBV, and HCV infections
* Drug and alcohol abuse
* Severe mental disorders
* Subjects who are planning radiologic exams involving in i.v. injection of iodinated contract materials
* Participation in another clinical trial
* Significant history or presence of cardiovascular, pulmonary, gastrointestinal, immunologic, endocrine, neurologic disorders
* Malignant diseases
* Previous exposure to any pharmaceutical antidiabetic agent
D: Inclusion Criteria:

* Ages 7-18 years.
* Greater than the 95th percentile body mass index for their age and gender.
* Children are in Tanner Stage I or IV or V.
* Normal Blood Pressure.
* Normal fasting glucose.
* Normal lipids.
* Menstruating girls must have completed their most recent period at least 2 weeks prior to blood draw.
* No recent illness, no chronic illnesses, no routine medications, no smoking or alcohol intake.
* Must pass the screening test done in Protocol #1.
* Must have higher values than normal for certain blood tests related to heart disease that were measured in Protocol #1.

Exclusion Criteria:

* Chronic active illnesses.
* Recent illnesses.
* Use of routine medications, vitamins, herbal remedies, oral contraceptive pills, or other over the counter medications within 4 weeks of blood draw.
* History of recent or chronic smoking.
* Currently pregnant.
* Impaired fasting glucose.
* Dyslipidemia.
* Actively in puberty.
* Weight greater than 300 pounds.
* Metal in the abdomen.
* History of being overweight greater than 5 years.

Answer: C