Please select the eligibility criteria that correspond to the clinical trial below.
Title: Restoring Insulin Secretion Pediatric Medication Study
Brief Summary: The RISE Pediatric Medication Study is a 2-arm, 4-center, clinical trial of children with prediabetes and early type 2 diabetes to address the hypothesis that aggressive glucose lowering will lead to recovery of beta-cell function that will be sustained after withdrawal of treatment. Pediatric participants (ages 10-19) will be randomized to one of the following treatment regimens: (1) metformin alone or (2) early intensive treatment with basal insulin glargine followed by metformin.

The primary clinical question RISE will address is: Are improvements in ß-cell function following 12 months of active treatment maintained for 3 months following the withdrawal of therapy? Secondary outcomes will assess durability of glucose tolerance following withdrawal of therapy, and whether biomarkers obtained in the fasting state predict parameters of ß-cell function, insulin sensitivity and glucose tolerance and the response to an intervention.


Options:
A: Inclusion Criteria:

1. Fasting plasma glucose 95-125 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus HbA1c ≤7.0%. There is no upper limit for the 2-hour glucose on OGTT.
2. Age 20-65 years
3. Body mass index (BMI) ≥25 kg/m2 but ≤50 kg/m2
4. Self-reported diabetes \<1 year in duration
5. Drug naïve (no prior to oral glucose lowering agent(s), insulin or other injectable glucose lowering agents)

Exclusion Criteria:

1. Underlying disease likely to limit life span and/or increase risk of intervention or an underlying condition that is likely to limit ability to participate in outcomes assessment
2. An underlying disease that affects glucose metabolism other than type 2 diabetes
3. Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications
4. Active infections
5. Renal disease (serum creatinine \>1.4 mg/dl for men; \>1.3 mg/dl for women) or serum potassium abnormality (\<3.4 or \>5.5 mmol/l)
6. Anemia (hemoglobin \<11 g/dl in women, \<12 g/dl in men) or known coagulopathy
7. Cardiovascular disease, including uncontrolled hypertension. Participants must be able to safely tolerate administration of intravenous fluids required during clamp studies.
8. History of conditions that may be precipitated or exacerbated by a study drug:

   1. Pancreatitis
   2. Serum alanine transaminase (ALT) more than 3 times the upper limit of normal
   3. Excessive alcohol intake
   4. Suboptimally treated thyroid disease
   5. Medullary carcinoma of the thyroid or MEN-2 (in participant or a family history)
   6. Hypertriglyceridemia (\>400 mg/dl despite treatment)
9. Conditions or behaviors likely to affect the conduct of the RISE Study

   1. Unable or unwilling to give informed consent
   2. Unable to adequately communicate with clinic staff
   3. Another household member is a participant or staff member in RISE
   4. Current, recent or anticipated participation in another intervention research project that would interfere with any of the interventions/outcomes in RISE
   5. Weight loss of \>5% in past three months for any reason other than post-partum weight loss. Participants taking weight loss drugs or using preparations taken for intended weight loss are excluded.
   6. Likely to move away from participating clinics in next two years
   7. Women of childbearing potential who are unwilling to use adequate contraception
   8. Current (or anticipated) pregnancy and lactation.
   9. Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE
10. Additional conditions may serve as criteria for exclusion at the discretion of the local site.
B: Inclusion Criteria:

* Recently diagnosed type 2 diabetes (within 3 years) on diet or IGT
* Fasting triglyceride levels \>140 and \< 400 mg/dl and values varying less than 35% between two screening measurements
* Normal liver function tests and white blood cell count

Exclusion Criteria:

* Type 2 Diabetes for \> 3 years or HbA1c ≥ 7.5
* Known or suspected Type 1 Diabetes
* Any diabetes medications in the past 3 weeks, TZD in the prior 3 months or prior regular use of insulin
* Creatinine \> 2.0 mg/dl or other evidence of active kidney disease
* Hepatic enzyme elevation \> 2x normal
* Known Nonalcoholic Fatty Liver Disease
* Malabsorption of fat or other nutrients, severe lactose intolerance or other significant gastrointestinal or pancreatic problems
* Recent history of nausea or vomiting
* Acute bacterial or viral illness or evidence of other active infection in the past 4 weeks
* A prior cardiovascular event, stable or unstable angina or other major illness in the past 6 months
* Current regular use of anti-inflammatory medications or antioxidants, including over the counter medications and high dose salicylates (\>1 g/day)
* Any lipid lowering therapy in the prior 3 weeks other than a statin medication. Subjects receiving a statin medication must be on a stable dose for at least 2 months prior to participation.
C: Inclusion Criteria:

* Informed consent
* Body mass index equal to or above 30 kg/m\^2
* Stable body weight (less than 5% self-reported change during the previous 3 months)
* Diagnosis of moderate or severe obstructive sleep apnoea (OSA)
* Unwilling or unable to use continuous positive airway pressure (CPAP) (or other positive airway pressure) treatment. No CPAP (or other positive airway pressure) treatment for at least four weeks prior to screening
* Ability and willingness to comply with all protocol procedures e.g. correct handling of trial product, compliance to visit schedule and dietary advice and complete trial related questionnaires

Exclusion Criteria:

* Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors or insulin within the last 3 months prior to screening
* Diagnosis of type 1 or type 2 diabetes per judgement of the investigator
* Glycosylated haemoglobin (HbA1c) equal to or above 6.5%
* Significant craniofacial abnormalities that may cause OSA
* Respiratory and neuromuscular diseases that could interfere with the results of the trial in the opinion of the investigator
* Use of central stimulants, hypnotics, mirtazepine, opioids, trazodone within the previous 3 months prior to screening
* Obesity induced by drug treatment
* Treatment with pramlintide, sibutramine, orlistat, zonisamide, topiramate or phenteremine within the last 3 month prior to screening
* Previous surgical treatment for obesity
* Screening calcitonin equal to or above 50 ng/L
* Familial or personal history of Multiple Endocrine Neoplasia type 2 or familial Medullary Thyroid Carcinoma
* Personal history of non-familial Medullary Thyroid Carcinoma
* History of chronic pancreatitis or idiopathic acute pancreatitis
* History of Major Depressive Disorder or suicide attempts
* Systolic blood pressure equal to or above 160 mmHg and/or diastolic blood pressure equal to or above 100 mmHg
D: Inclusion Criteria:

1. Fasting plasma glucose ≥90 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus laboratory-based HbA1c ≤8.0% if treatment naïve. There is no upper limit for the 2-hour glucose on OGTT. In those taking metformin laboratory-based HbA1c must be ≤7.5% if on metformin for \<3 months and ≤7.0% if on metformin for 3-6 months.
2. Age 10-19 years
3. Pubertal development Tanner stage \>1 as defined by breast stage \>1 in girls, and testes \>3 cc's in boys.
4. Body mass index (BMI) ≥85th percentile but ≤50 kg/m2
5. Self-reported diabetes \<6 months in duration
6. Treatment with metformin for \<6 months preceding screening

Exclusion Criteria:

1. Underlying disease likely to limit life span and/or increase risk of intervention or an underlying condition that is likely to limit ability to participate in outcomes assessment
2. An underlying disease that affects glucose metabolism other than type 2 diabetes mellitus
3. Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications
4. Treatment with insulin for \>1 week preceding screening
5. Active infections
6. Renal disease (serum creatinine \>1.2 mg/dl) or serum potassium abnormality (\<3.4 or \>5.5 mmol/l)
7. Anemia (hemoglobin \<11 g/dl in girls, \<12 g/dl in boys) or known coagulopathy
8. Cardiovascular disease, including uncontrolled hypertension defined as average systolic or diastolic blood pressure \> 99 percentile for age or \>135/90, despite adequately prescribed antihypertensive medications. Participants must be able to safely tolerate administration of intravenous fluids required during clamp studies.
9. History of conditions that may be precipitated or exacerbated by a study drug:

   1. Serum alanine transaminase (ALT) more than 3 times the upper limit of normal
   2. Excessive alcohol intake
   3. Sub-optimally treated thyroid disease
10. Conditions or behaviors likely to affect the conduct of the RISE Study

    1. Participant and/or parents unable or unwilling to give informed consent
    2. Participant and/or parents unable to adequately communicate with clinic staff
    3. Another household member is a participant or staff member in RISE
    4. Current, recent or anticipated participation in another intervention research project that would interfere with any of the interventions/outcomes in RISE
    5. Weight loss of ≥5% of body weight in the past 3 months for any reason other than post-partum weight loss. Participants taking weight loss drugs or using preparations taken for intended weight loss are excluded.
    6. Likely to move away from participating clinics in next 2 years
    7. Current (or anticipated) pregnancy and lactation.
    8. A pregnancy that was completed less than 6 months prior to screening.
    9. Breast feeding within 6 months prior to screening.
    10. Women of childbearing potential who are unwilling to use adequate contraception
    11. Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE
11. Additional conditions may serve as criteria for exclusion at the discretion of the local site.

Answer: D