Intervention: Metformin
Trial phase: Not Applicable
ATC code: A10BA02 | A10BD02 | A10BD03 | A10BD05 | A10BD07 | A10BD08 | A10BD10 | A10BD11 | A10BD13 | A10BD14 | A10BD15 | A10BD16 | A10BD17 | A10BD18 | A10BD20 | A10BD22 | A10BD23 | A10BD25 | A10BD26 | A10BD27
SMILES: CN(C)C(=N)NC(=N)N
Sex: All
Age groups: Child | Adult | Older Adult
Healthy volunteers: Accepts Healthy Volunteers
Participants at risk: 10
Group description: Doses will be increased incrementally. Decisions to escalate the metformin dose will be made based upon tolerability of side effects as described in the schedule of evaluations to follow. All subjects will be monitored for safety while receiving metformin. Any participant with blood glucose of <60mg/dl at any time while receiving metformin will have therapy stopped and will be withdrawn from the study.

For children <50kg:

Baseline:250mg po qd, Week 2:250mg po bid, Week 4:500mg po AM/250mg po PM, Week 8:500mg po bid.

For children ≥50kg:

Baseline:500mg po qd, Week 2:500mg po bid, Week 4:1000mg po AM/500mg po PM, Week 8:1000mg po bid.

For adults:

Baseline:500mg po qd,Week2:500mg po bid,Week 4:1000mg po AM/500mg po PM,Week 8:1000mg po bid.

Metformin
Eligibility criteria:
Pediatric Inclusion Criteria:

Children 10-17 years.
Both genders (male and female)
All children must have a Primary Care Physician and/or an Endocrinologist who must be aware that the child under their care will be part of the study.
All children must have a Primary Care Physician and/or an Endocrinologist who is considering initiating metformin therapy now or in the near future as part of standard clinical care.
Naïve to metformin.
Either: Prediabetic children Or diabetic children under good glycemic control

Pediatric Exclusion Criteria:

Children ages 10-17 who do not have parental consent and/or do not give assent
Children living in foster care
Children with allergies to foods in the breakfast menu
Children who currently consume any alcohol
Children on current antidiabetic medication or those who have been on any antidiabetic medication in the 3 months prior to enrolment
Children with a history of /or concurrent chronic disease (eg. heart, kidney, liver disease or any type of malignancy or pre-malignant condition) that required hospitalization within the last 6 months
Pregnancy
Refusal by a female participant who is of child bearing potential and sexually active to use contraceptive methods such as oral contraceptive pills, barrier methods and abstinence
Children weighing less than 36 kg
Children with any condition that increases the risk of lactic acidosis (e.g. cancer, infection, congestive heart failure, renal disease )
Children with history of recent hospitalization for surgery, dehydration, sepsis, hypoxemia (within the past 6 months)
Children with history of weight loss, polyuria and polydipsia
Children who are currently enrolled in a weight management program
Children with known hypersensitivity to metformin
Children with a fasting blood glucose of >180mg/dl
Children with a HbA1c level of ≥7%
Children with glycosuria
Children with clinical or laboratory evidence of hepatic disease- transaminase levels three times the upper normal range (Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)) and/or a increased level of Gamma-glutamyltransferase (GGT), Prothrombin Time (PT), International Normalized Ratio (INR) from the reference normal range and a serum albumin less than the reference normal range of the Johns Hopkins Clinical Laboratories.
If iodinated contrast is used on a participant, due to possible acute alteration of renal function resulting in increased risk of lactic acidosis, the participant will be excluded.

Children with renal impairment

In children >50kg, renal impairment is defined by a serum creatinine 1.4 mg/dl or higher in females or 1.5mg/dl or higher in males OR estimated Glomerular Filtration Rates (eGFR) ≤60mL/min by the Schwartz formula.
In children <50kg, renal impairment is defined by eGFR <100 mL/min by the Schwartz formula.
Children with acid-base disturbance as defined by serum bicarbonate levels less than 20mEq/L or greater than 29mEq/L.

Adult Inclusion Criteria:

Adults 18-79 years
Both genders (male and female)
All participants must have a Primary Care Physician and/or an Endocrinologist who must be aware that the adult under their care will be part of the study
All participants must have a Primary Care Physician and/or an Endocrinologist who is considering initiating metformin therapy now or in the near future as part of standard clinical care.
Naive to metformin
EITHER: Prediabetic adults OR diabetic adults, under fair glycemic control:

Adult Exclusion Criteria:

Pregnancy
Adults who are not able to understand the Informed Consent document and who are unwilling to do the study
Adults with allergies to any of the foods in the breakfast menu
Adults on current antidiabetic medication or on any antidiabetic medication in the 3 months prior to enrolment.
Adults with a history of /or concurrent chronic disease (e.g. heart, kidney, liver disease or any type of malignancy or pre-malignant condition) that required hospitalization within the last 6 months
Refusal by a female participant who is of child bearing potential and sexually active to use contraceptive methods such as oral contraceptive pills, barrier methods and abstinence
Adults with excessive current intake of alcohol (>2 drinks/day for males and >1 drink/day for females)
Adults who have engaged in binge drinking (>5 drinks within a 2 hour period) in the last 3 months
Adults with history of recent hospitalization for surgery, dehydration, sepsis, hypoxemia (past 6 months)
Hypersensitivity to metformin.
Adults with fasting blood glucose of >180mg/dl.
Adults with HbA1c level of ≥8%
Adults with glycosuria.
Adults with any condition that increases the risk of lactic acidosis (e.g. cancer, infection, congestive heart failure, renal disease )
Adults with clinical or laboratory evidence of hepatic disease- transaminase levels three times the upper normal range (AST and ALT) and/or a increased level of GGT, PT, INR from the reference normal range and a serum albumin less than the reference normal range of the Johns Hopkins Clinical Laboratories.
If iodinated contrast is used on a participant, due to possible acute alteration of renal function resulting in increased risk of lactic acidosis, the adult participant will be excluded.
Adults with renal impairment as defined by a serum creatinine 1.4 mg/dl or higher in females or 1.5mg/dl or higher in males OR estimated Glomerular Filtration Rates (eGFR) ≤60mL/min by Modification of Diet in Renal Disease (MDRD) formula.
Adults with acid-base disturbance as defined as serum bicarbonate levels less than 20mEq/L or greater than 29mEq/L.

Adult Obese Control Inclusion Criteria:

Age 18-79
Both genders (male and female)
BMI > 30 kg/m2

Adult Obese Control Exclusion Criteria:

Subjects previously or currently on any diabetes medication, including metformin, will be excluded.
Pregnancy
Subjects with history of or concurrent chronic disease (e.g. heart, kidney, liver disease or any type of malignancy or pre-malignant condition) that required hospitalization within the last 6 months will be excluded.
Adults with allergies to any of the foods in the breakfast menu
Adults with excessive current intake of alcohol (>2 drinks/day for males and >1 drink/day for females)
Adults who have engaged in binge drinking (>5 drinks within a 2 hour period) in the last 3 months