Free Fatty Acids, Body Weight, and Growth Hormones Secretion in Children

Obese children and adults display lower spontaneous and stimulated growth hormone (GH)
secretion. It is presumed that dysregulation of some of the factors normally involved in
controlling GH secretion underlies the hyposomatotropinemia of obesity, given that GH
production usually normalizes after weight loss. Free fatty acids (FFA) are one factor
thought to be involved in regulation of GH secretion. Niacin is a nicotinic acid derivative
that inhibits lipolysis and lowers circulating FFA concentrations. Nicotinic acid derivatives
have been used in several adult studies examining GH secretion. Specifically in obese adults,
inhibition of lipolysis has been found to increase spontaneous and stimulated GH production,
presumably due to direct effects of FFA on hypothalamic GH-regulating neurons. Thus far no
pediatric studies have examined the effects of niacin on GH secretion, and there is only one
small pediatric study of normal weight prepubertal children growing at the 5th-10th
percentile in height has tested the effects of lipolytic inhibition by acipimox (a related
medication also derived from nicotinic acid) on GH secretion. There are no data in obese
children demonstrating the effects of inhibition of lipolysis on GH secretion.

We propose to investigate one of the mechanisms through which high adiposity alters GH
secretion in children by testing the effects of inhibiting lipolysis. First we will conduct
dose establishing studies to determine the appropriate dose of niacin needed to suppress FFA
concentrations in children. We will then conduct the main study, designed as a pilot
randomized, double-blind placebo controlled trial of niacin administration, to assess its
effects on stimulated GH secretion. We hypothesize that in overweight children niacin will
lead to a fall in free fatty acid concentrations and consequently a rise in stimulated GH
secretion. We further hypothesize that the overweight subjects will demonstrate stimulated GH
secretion profiles with niacin similar to those of control subjects who receive placebo. We
expect this pilot study may help improve how diagnostic testing is carried out for growth
hormone deficiency in children.

- INCLUSION CRITERIA:

Subjects will qualify for the overweight group for the dose-establishing studies 1 and 2
and main study) if they meet the following criteria:

1. Good general health.

2. Age greater than or equal to 7 and less than 15 years.

3. Tanner stage I, II or III for the breast among girls and testes less than10 mL for
boys based upon an examination by a trained physician or nurse practitioner.

4. Weight > 30 kg.

5. Fasting plasma glucose < 100 mg/dL, 2 hour post-dextrose glucose < 140 mg/dL, and
HgbA1C less than or equal to 6.4%.

6. Females who are age 10 or greater must have a negative pregnancy test.

7. Body mass index greater than or eqaul to 95th percentile determined by Centers for
Disease Control age and sex specific data (given that most pathology of obesity does
not usually emerge until children cross the 95th percentile).

8. No evidence of growth failure as defined as height > 5th percentile.

Subjects will qualify for the non-overweight control group (for the main study only) if
they meet the following criteria:

1. Recommended by a pediatric endocrinologist to undergo GH stimulation testing to
establish the diagnosis of GH-deficiency.

2. Good general health.

3. Age greater than or equal to 7 and less than15 years.

4. Tanner stage I, II or III for the breast among girls and testes less than 10 mL for
boys based upon an examination by a trained physician or nurse practitioner.

5. Weight > 30 kg.

6. Fasting plasma glucose < 100 mg/dL, 2 hour post-dextrose glucose < 140 mg/dL, and
HgbA1C less than or equal to 6.4%.

7. Females who are age 10 or greater must have a negative pregnancy test.

8. Height < 5th percentile.

9. BMI between the 5th and 85th percentiles determined by Centers for Disease Control age
and sex specific data.

10. Birth weight and length not consistent with small for gestational age (SGA) criteria
or a history of intrauterine growth restriction (IUGR) based on recall history.

EXCLUSION CRITERIA (for the dose-establishing sutides 1 and 2, and the main study):

Subjects will be excluded if they have any of the following:

1. Baseline creatinine greater than or equal to 1.0 mg/dl.

2. Significant cardiac or pulmonary disease likely to or resulting in hypoxia or
decreased perfusion.

3. Hepatic disease with elevated liver function tests (ALT or AST)greater than or equal
to 1.5 the upper limits of normal.

4. Pregnancy.

5. Evidence for impaired glucose tolerance or Type 2 diabetes, including fasting plasma
glucose greater than or equal to 100 mg/dL, 2 hour post-dextrose glucose greater than
or equal to 140 mg/dL, or HgbA1C > 6.4%.

6. Presence of other endocrinologic disorders leading to obesity (e.g. Cushing Syndrome).

7. Any disorder that is known to affect GH secretion (e.g. untreated hypothyroidism) or
use of any medication known to affect GH levels (including glucocorticoids and GH
itself).

8. Any other disorder that is known to affect stature including skeletal dysplasias.

9. Recent use (within two years) of anorexiant medications, stimulant medications, or
other medications felt to impact growth.

10. Individuals who have, or whose parent or guardians have, current substance abuse or a
psychiatric disorder or other condition that, in the opinion of the investigators,
would impede competence or compliance or possibly hinder completion of the study.

11. Individuals receiving medical treatment other than diet for hypertension or
dyslipidemia.

12. Individuals with evidence of precocious puberty as defined as palpable breast tissue
noted in females before the age of 7, testicular size greater than or equal to 4cc in
males before the age of 9, or bone age advancement more than 2 SD for chronologic age.

13. Individuals receiving androgen or estrogen hormone therapy.