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

Background:

- Overweight and obese children and adults often have lower levels of growth hormone in the blood. Regulation of growth hormone may be tied to weight and free fatty acids in the blood. Current tests of growth hormone (such as those used when evaluating the heights of children who are markedly shorter than other children of comparable age) may be affected by other factors, including obesity. Researchers are interested in evaluating the levels of growth hormone and free fatty acids in the blood of children between 7 and 14 years of age who weigh more than children of a comparable age, or who are shorter than other children of a comparable age and have been recommended for growth hormone testing as part of an evaluation for their height.

Objectives:

- To determine the effect of changes in free fatty acids in the blood on changes in growth hormone secretion in overweight or shorter children and young adolescents.

Eligibility:

- Children and adolescents between 7 and 14 years of age who weigh more than or are shorter than other children of a comparable age and do not have any medical illnesses.

Design:

* Participants will have two study visits, one of which will be a half day screening visit in the outpatient clinic and one of which will require 2 nights as an inpatient at the National Institutes of Health Clinical Center.
* Participants should not eat or drink anything except water after 10 PM the night before or on the morning of the screening visit.
* At the screening visit, participants will have a physical examination and medical history, provide blood and urine samples, have an oral glucose tolerance test (to check blood sugar levels), and have an x-ray of the left hand to check bone age.
* The inpatient study visit will involve a physical examination and medical history, a full x-ray scan to study body fat and muscle, frequent blood tests throughout the visit, and various medications to stimulate growth hormone production and lower levels of free fatty acids in the blood.

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.

Eligibility Criteria:
* 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.