Metabolic Impact of Fructose Restriction in Obese Children

Recent studies suggest that specific types of macronutrients in the diet may have selective
effects on nutrient absorption, insulin sensitivity, and lipid metabolism. Elucidation of the
metabolic impact of specific dietary components may well result in improved efficacy of
lifestyle approaches to reduce obesity and metabolic diseases. Despite similar fructose
consumption, the phenotype of co-morbidities is different between African Americans and
Latinos. Latino and Caucasian children manifest worsened dyslipidemia and non-alcoholic fatty
liver disease (NAFLD), while African American children manifest worsened insulin resistance
and hypertension. We have also documented in adults that a reduction in de novo lipogenesis
(DNL; production of new lipids) in the liver and liver fat content, and improvement in
hepatic insulin sensitivity were achieved by substitution of complex carbohydrate for
fructose; but these changes appeared less dramatic in African American compared to Latino or
Caucasian subjects. These divergent findings suggest ethnic and race-specific differences of
fructose metabolism and disposition.

To determine whether fructose is a contributor to metabolic co-morbidity in children, we will
conduct a convenience cohort within-subject intervention with repeated measures, stratified
by racial/ethnic group (Latinos vs. African Americans vs. Caucasians). The intervention will
consist of restricting fructose ingestion only to naturally-occurring fructose in fruits and
vegetables (approximately 15 gm/day for 10 days), by substituting complex carbohydrate for
excess dietary fructose, while maintaining neutral energy balance. We anticipate fructose
restriction to differentially improve co-morbidities in different racial/ethnic groups.

Inclusion Criteria:

- African-American, Latino, and Caucasian boys and girls. Ethnicity is to be determined
by self-report. Utilizing the US Census Bureau procedures, participants will be asked
two questions, the first regarding ethnicity and the second on race. Subjects will be
given the opportunity to select more than one racial category.

- Ages 8 to 18 yr. The minimum age cutoff is due to our desire not to sedate younger
children for the magnetic resonance spectroscopy scan or magnetic resonance scan (MRS,
MRI). We chose to study these groups because they are most affected by metabolic
syndrome and manifest the greatest morbidities; yet their presentations are different
from each other.

- The following criteria are modified from the National Cholesterol Education Program's
Adult Treatment Panel and the World Health Organization definition of metabolic
syndrome. Waist circumference is not an adequate predictor of visceral adiposity in
children. Also, no normative values have been developed nor is this measurement
consistent between racial and ethnic groups. Body mass index (BMI), however,
correlates strongly with both visceral lipid depot and blood pressure. The definition
of hypertension is greater than the 95th percentile for sex and age as designated in
the 1996 Task Force Report on High Blood Pressure in Children and Adolescents.

1. Obesity, as defined by BMI z-score of 2.0 or greater, or above the 97th
percentile for age and sex; and weight ≥40 kg.

2. Hyperinsulinemia (fasting insulin >15 µU/mL), or insulin resistant (HOMA > 4.3).
See details below.

3. At least one of the following: systolic blood pressure above the 95th percentile
for age and sex, or triglyceride level above the 95th percentile for age, sex and
race or ethnic group as established by the 1998 National Heart, Lung, and Blood
Institute Growth and Health Study.

Exclusion Criteria:

- History of disorders other than obesity that may affect insulin levels, such as
Cushing's syndrome, diabetes mellitus, or depression.

- Medications that may affect insulin sensitivity or hepatic lipid content, e.g.
metformin, steroids, atypical antipsychotics, anti depressants, statins, Vitamin E,
thyroid medications, anti-hypertensives, weight loss medications, oral contraceptives.

- Pregnancy or lactation.

- Surgical procedures for obesity.

- History consistent with obstructive sleep apnea.

- Implants including intracranial surgical clips, pacemakers, and other metals or
implants that preclude MR scanning.

- Claustrophobia.

- Inability to fit within the MR bore: shoulder to shoulder width of greater than 58 cm
or anterior-posterior length greater than 35 cm (magnet bore size limitation).

- Weight greater than 320 pounds (MRS table weight limitation).

- Eating disorders.

- Smoking or alcohol use. Subjects will answer the two questions on the Alcohol Query
Form. Any consumption of more than 2 drinks per month will

- Vegan diet.

- All subjects with known diabetes mellitus according to the 1997 ADA criteria will be
excluded. However, subjects with known impaired glucose tolerance (fasting glucose
101-125, and 2-hour post-prandial glucose level between 141-200) can remain eligible.

- Syndromic patients (e.g. Prader-Willi, Bardet-Biedl) will be excluded, as it is likely
that the reasons for their obesity may be neurologic or single-point mutations, and
are likely to be different from those causing the Metabolic Syndrome.

- Subjects who are found to be hypothyroid by clinical exam or by evaluation of thyroid
function tests on first visit to the WATCH Clinic will receive L-thyroxine for three
months, with documentation of adequate replacement, prior to enrollment in the
protocol.

- Subjects with a history of hepatitis will be excluded from the study. However,
patients with NAFLD, as determined by Dr. P. Rosenthal (Ped. Hepatology, UCSF), may
participate. Upper cutoffs for AST and ALT will be 5 times the upper limit of normal
for the UCSF laboratory.

- Subjects with any history of renal disease will be excluded.

- Subjects who have a fever or an active infection will be postponed until their
infection remits.

- Emancipated minors will be excluded, as there will be no parental supervision and
monitoring over the subject's diet during the 9 days of fructose restriction.

- Females who have achieved menarche will have a urine pregnancy test at the time of
their DEXA scans. A positive pregnancy test will lead to exclusion of the data from
further analysis. Results of a positive pregnancy test will be transmitted to the
minor only, and the parents will be told only that the subject does not qualify for
the study.