FGF21 and Fructose Challenge in Humans

Participation in this study involves fasting overnight, drinking a sweet beverage, and
several blood draws through an IV line. Each subject may drink up to 10 different sweet
beverages, separated by 2 weeks.

Inclusion criteria for lean subjects:

- Men and women ages 18-60

- BMI 19-25 kg/m2; 19-23 for Asian subjects

- Stable weight (variation < 3 kg within 6 months of screening visit)

- Ability to give informed consent

- Ability to follow verbal and written instructions in English

- Use of medically approved form of contraception (monophasic oral contraception, intra
uterine device, surgical sterilization or 2 combined barrier methods)

Specific exclusion criteria for lean subjects:

- Fasting blood glucose >100; 2 hr OGTT blood glucose >140

- Fasting triglycerides >150

Inclusion criteria for metabolic syndrome subjects:

3 or more of the following (based on joint scientific statement by Alberti et al, 2009:

- Fasting triglycerides >150 mg/dl (or on treatment for elevated triglycerides)

- HDL cholesterol <40 mg/dl in men or <50 mg/dl in women

- Blood pressure > 130/85 (or antihypertensive treatment in a subject with history of
hypertension)

- Fasting BG >100

- Elevated waist circumference ** see below for race and ethnic specifications

Men Women

- Asian or Central, South or Native American > 90 cm > 80 cm

- Non-Asian, Non-Latino United States > 102 cm > 88 cm

General Exclusion criteria

- Type 1 or type 2 diabetes mellitus diagnosed according to American Diabetes
Association criteria

- Coronary heart disease (history of myocardial infarction, unstable angina pectoris, or
congestive heart failure)

- Uncontrolled hypertension (BP > 160/100 mmHg on or off antihypertensive medication)

- Marijuana or intravenous drug use

- Recent weight loss (> 3 kg within 6 months of the screening visit)

- Gastroparesis

- Inflammatory or irritable bowel disease

- Malignancy treated with chemotherapy within the past 3 years

- Depression or psychosis requiring hospitalization

- Renal insufficiency (creatinine clearance < 40 ml/min)

- Transaminases > 2x above the normal range

- Known liver disease

- Pregnancy within 6 months of the screening visit

- Lactation

- Failure to use medically approved contraceptive methods

- History of surgery for the treatment of obesity (gastric banding, gastric bypass,
gastric stapling)

- Change in dose of thyroid hormone or antithyroidal medication within 3 months of
screening visit

- History of alcohol abuse within the past 5 years

- Fructose intolerance

Exclusionary medications:

- Oral steroids

- Metformin

- Weight loss medications including nonprescription supplements