Metformin at the Cellular Level and Dosing for Diabetes Mellitus (DM)

Our studies have shown that metformin acts at the cellular level by acting on a target
protein, Cyclic amine monophosphate-Response Binding Elements (CREB) binding protein or CREP
Binding Protein (CBP). Patients are treated with many different doses of metformin, some
patients respond well to low doses while others require much higher doses. The investigators
do not understand why this may be and are interested in knowing if the investigators can
treat patents effectively with low doses. What the investigators do not know is how this
process is affected when the dose of the metformin is increased or changed. Changes in
metformin's target protein will provide evidence on the effectiveness of the dose.

Also, currently the same doses of metformin are often used in both children and adults, but
it is possible that the dose of metformin should be based on age and weight. Understanding
how CBP works could potentially help us to tailor metformin treatment individually for
patients based on their age, weight and CBP response.

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