Please select the eligibility criteria that correspond to the clinical trial below.
Title: Glycemic Control in Children and Adolescents With Double Diabetes: Trial of Optimized Insulin-Metformin Regimen
Brief Summary: The significance of this project is to investigate the effects of adjunctive metformin therapy in children and adolescents with double diabetes. Double diabetes describes a clinical state where an individual possesses features of both type 1 and type 2 diabetes. There is a paucity of data on the role of adjunctive metformin therapy in children and adolescents with double diabetes. To help fill this knowledge gap, the investigators propose a randomized, double-blind, placebo-controlled trial of metformin in double diabetes. Specifically, the investigators will evaluate changes in hemoglobin A1c and anthropometry in patients with a diagnosis of type 1 diabetes who also have features of type 2 diabetes or metabolic syndrome as well as patients with type 2 diabetes who possess diabetes-associated autoantibodies. This will help determine the safety profile, and efficacy of adjunctive metformin therapy in these subjects.


Options:
A: Inclusion Criteria:

* You are healthy.
* You are not pregnant or nursing.
* You are between 18 and 60 years of age.
* You have a body mass index, calculated from your height and weight, of 30 to 40 kg/m2.

Exclusion Criteria:

* You take chronic medications except hormone replacement or contraception.
* You are a woman and are unwilling to use effective contraception during the trial.
* You have blood pressure higher than 150/90.
* You have heart disease.
* You have urinary symptoms from an enlarged prostate.
* You have gained or lost more than 10 pounds in the last 6 months.
* You have used a monoamine oxidase inhibitor medication in the last month.
* You have high or low thyroid function that has not been controlled in the normal range for at least 2 months.
* You have heart disease or a history of stroke.
* You have a known sensitivity to E. coli or E. coli derived products.
B: Inclusion Criteria:

1. Clinical diagnosis of presumed autoimmune type 1 diabetes (T1D) as indicated by age of diagnosis \<10 years or documented positive diabetes-related autoantibodies.

   a. Note: For randomization, presence of at least one of the diabetes-related autoantibodies \[Insulin autoantibodies (IAA) at diagnosis prior to initiation of insulin, Islet cell antibodies (ICA), Anti-GAD (GAD65), Anti-IA2 (IA2), Zinc Transporter 8 (ZnT8)\] must be documented either from medical records or new laboratory measurement (IAA and ICA not measured by central lab) sent to central lab for participants who were ≥10 years old at diagnosis.
2. Age: 12 to \<20 years.
3. Duration of type 1 diabetes: ≥1 years.
4. Current insulin regimen involves either use of an insulin pump or multiple daily injections of insulin (at least 3 shots per day) for the last three months, with no plans to switch the modality of insulin administration during the next 6 months (e.g., injection user switching to a pump, pump user switching to injections).
5. Hemoglobin A1c: 7.5% - \<10.0% from point of care measurement or local lab on day of screening visit or within 1 month prior.
6. BMI: ≥85th percentile adjusted for age and sex .
7. Total daily dose of insulin: ≥0.8 units per kg per day.
8. Average of ≥3 Self-Monitoring Blood Glucose (SMBG) tests per day prior to initiating study and from download of study-provided blood glucose meter following screening visit.
9. Available for at least 6 months of follow-up, has home phone (or access to phone), and willing to be contacted by clinical site staff.
10. Expected to comply with protocol in investigator's judgment.

Exclusion Criteria:

1. Use of non-insulin medications for blood glucose control within prior 6 months or planning to use within next 6 months (other than study drug).
2. Use of medications for weight reduction (such as: Belviq (lorcaserin), Qsymia (Phentermine + topiramate), Orlistat (xenical)) within the prior 6 months or planning to use within next 6 months.
3. Use of a medication such as stimulants, psychotropic agents and oral/inhaled glucocorticoids that could affect weight gain or glycemic control of T1D or planning to use within the next 6 months.
4. Any condition that in the judgment of the investigator will adversely affect the completion of the protocol.
5. Females: pregnant, lactating, or intending to become pregnant within the next 34 weeks

   * A negative urine pregnancy test will be required for all females An effective contraceptive method or abstinence will be required for all females who have experienced menarche
   * Requirements regarding pregnancy testing prior to enrollment and monitoring for pregnancy over the course of the study may be further defined by each individual Institutional Review Board (IRB)
6. Clinical diagnosis of celiac disease that is in poor control as defined by most recent tissue transglutaminase (tTG) that is in the abnormal range.
7. History of ≥1 diabetic ketoacidosis events in the past 3 months.
8. History of ≥1 severe hypoglycemic events (cognitive impairment that required assistance to treat) in the past 3 months.
9. History of anemia or vitamin B12 deficiency in the past 2 years.
10. Participation in an intervention study in the past 3 months.
C: Inclusion Criteria:

A. General inclusion criteria

1. Ten to 20 years of age.
2. Pubertal (Tanner stages 2-5, by examination).
3. Hemoglobin A1c level of \> 8.0% in the 6 months prior to enrollment.
4. All subjects must have access to a computer.

B. Specific inclusion criteria: \[Subjects could have either #1, or #2\].

1. Subjects with clinical and biochemical features of T2DM of \> 6mo duration who also have positive T1DM antibodies

   * Clinical features: acanthosis nigricans, BMI \>85%
   * Biochemical: evidence of insulin resistance at diagnosis
   * fasting insulin \>27 uIU/mL(normal range 6-27) at a fasting blood glucose of ≥ 126 mg/dL, or
   * fasting c-peptide level of \> 7.1 ng/mL (normal range 0.9 - 7.1), or
   * Homeostasis model of insulin resistance of \>3.16
2. Patients with T1DM of \> one yr duration with BMI \>85%

   * Presentation with ketoacidosis at diagnosis
   * C-peptide \<0.9 ng/mL (normal range 0.9 - 7.1),or (insulin \< 6 uIU/mL) (NR 6-27) at diagnosis (when blood glucose is ≥ 126 mg/dL)
   * Can be antibody positive or negative
   * Increased insulin requirement (\>2 Units/kg/day)

Exclusion Criteria:

1. Subjects on weight altering medications, such as orlistat.
2. Subjects with eating disorder
3. Subjects on medications other than insulin and or metformin that may affect blood glucose level.
4. Subjects with abnormal hepatic function tests.
5. Subjects with nephropathy, defined in this case as an overnight albumin excretion rate of \>200 mcg/min using a first morning urine sample collection.
6. Subjects with recurrent diabetes ketoacidosis (more than 2 episodes in the past 12 months), or recurrent severe hypoglycemia (more than 2 episodes of hypoglycemia with altered level of consciousness, requiring assistance to treat in the past year).
7. Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures.
8. Known or suspected allergy to metformin.
9. The receipt of any investigational drug within 6 months prior to this trial.
10. Active malignant neoplasms.
11. No access to a computer.
12. Subjects currently taking metformin for clinical purposes are not eligible to be enrolled in this study.
D: * INCLUSION CRITERIA:

Volunteers will qualify for inclusion under this protocol if they meet the following criteria:

1. Good general health. Individuals with renal, hepatic, most endocrinologic (e.g. hypothyroidism, or Cushing syndrome), or pulmonary disorders (other than mild asthma not requiring chronic medication) will be excluded.
2. For obese subjects, body mass index for age above the 85th percentile (determined by NHANES I age-, sex-, and race-special data). For normal weight subjects of obese parents, body mass index (determined by NHANES I age-, sex-, and race- specific data) between the 5th and 85th percentile and both parents' current body mass index above 25 kg/m(2), or a history of a body mass index above 25 kg/m(2).
3. No significant psychiatric illness.
4. At initial visit, Tanner I (prepubertal) or Tanner II (early pubertal) pubic hair and breast stage of development for girls, and Tanner I or Tanner II pubic hair and testes size (6ml) for boys.
5. Subjects must be able to undergo MRI. Volunteers with metal in their bodies that are contraindications for MRI will be excluded. These include cardiac pacemakers, neural pacemakers, aneurysmal clips, shrapnel, ocular foreign bodies, cochlear implants, non-detachable electronic or electromechanical devices (such as infusion pumps, nerve stimulators, bone growth stimulators, etc.).
6. Age 6 to12 years at the start of the study.
7. For girls who have been followed to an age when they are menstruating (or are of an age when pregnancy is a possibility), a negative pregnancy test.
8. Race of all 4 grandparents self-identified either as all Caucasian or all African American.

Answer: C