The AgRP and GH/IGF-1 Axis in Children

Agouti-related Peptide (AgRP) and the GH/IGF-1 Axis in Children

Recent data support the existence of a GH-Agouti-related peptide (AgRP) axis. The neuropeptide AgRP promotes food intake and has important effects on energy homeostasis. Recent evidence suggest that GH stimulates AgRP and AgRP may mediate some of GH's important nutritional and metabolic effects. main goals of this project are to characterize, for the first time, plasma levels of AgRP in children and to determine how these relate to GH and IGF-1 levels, age, body composition, clinical and other endocrine parameters. To accomplish this, we will conduct two studies, one being a cross-sectional study that will measure AgRP levels in 140 healthy children ages 5-17 and the second being a prospective study that will measure the change in plasma AgRP levels in response to GH treatment in 16 children who receive this as part of their clinical care for GH deficiency or short stature.

Protocol 1 This will be a cross-sectional study in 140 healthy children. Participation will include one visit that will take place between 8-9 am and after a fast from midnight the night before.

Procedures at the visit will include:

1. Review of medical history
2. Anthropometrics measurements: Weight, height, waist and hip circumferences.
3. Collection of information from medical record including growth records and physical examination findings including features relevant to pubertal stage in all children and onset of menses in females.
4. Assessment of pubertal status and Tanner stage based on physical examination.
5. Collection of information on diet, activity level and sleep.
6. Blood Sampling: venous blood will be sampled from a peripheral vein for measurement of AgRP, GH, IGF-1, leptin, SOb-R, triglycerides, insulin, glucose, testosterone(males), estradiol(females), DHEAS and cortisol levels. Insulin and glucose levels will be used to assess insulin resistance by HOMA & QUICKI.

Protocol 2 This will be a prospective study in 16 children who will be studied before and at 4 time points (1 week, 2 weeks, 1 month and 2 months) after starting GH treatment as part of their clinical care. This protocol will study subjects Groups 2 and 3. Growth hormone will not be prescribed as part of this study. Children will be treated clinically with GH as prescribed by their Pediatric Endocrinologist for FDA approved indications and according to standard guidelines for dosing for treatment of GH deficiency in children.

Each visit that will take place between 8-9 am and after a fast from midnight the night before.

Procedures at each visit will include:

1. Review of medical history
2. Anthropometrics measurements: Weight, height, waist and hip circumferences, skinfold thicknesses.
3. Collection of information from medical record including growth records and physical examination findings including features relevant to pubertal stage in all children and onset of menses in females. GH dose and compliance will be recorded at follow up visits.
4. Collection of information on diet, activity level and sleep.
5. Blood Sampling: Venous blood will be sampled at a peripheral vein for:

Baseline (pre-GH treatment): measurement of AgRP, GH, IGF-1, IGFBP-3, leptin, SOb-R, triglycerides, insulin and glucose, testosterone(males), estradiol(females), DHEAS and cortisol levels.

Follow up visits on growth hormone: measurement of AgRP, IGF-1, IGFBP-3, leptin, SOb-R, triglycerides, insulin, glucose and cortisol levels.

Insulin and glucose levels will be used to assess insulin resistance by HOMA & QUICKI.

Healthy children

Inclusion Criteria:

1. Ambulatory male and female children aged 5-17 years
2. Normal weight at birth
3. Height between the 3rd and 99th percentiles of the mean as per the CDC growth percentiles.

Exclusion Criteria:

1. Genetic defects, chronic illnesses.
2. Current prescription medication use
3. Use of glucocorticoids, thyroid hormone or medications that may affect the GH-IGF-1 axis within 6 months of study entry.

Children with GH deficiency:

Inclusion Criteria:

1. Ambulatory male and female children aged 5-9 years who are prepubertal
2. Normal weight at birth
3. Growth failure
4. Peak GH response to 2 GH stimulation tests < 10 ng/ml
5. Normal renal and liver function

Exclusion criteria:

1. Multiple pituitary hormone deficiencies,
2. GH deficiency or poor growth associated with any acute or chronic medical condition such as renal disease or Turner's syndrome.
3. History of diabetes or malignancy
4. Use of glucocorticoids or medications known to affect the GH-IGF-1 axis within 6 months of study entry.

Children with idiopathic Short Stature:

Inclusion Criteria:

1. Ambulatory male and female children aged 5-9 years who are prepubertal
2. Normal weight at birth
3. Height >2.25 SD below mean for age
4. Peak GH response to 2 stimulation tests >10 ng/ml or normal IGF-1 and IGFBP-3 levels
5. No prior supplemental growth hormone exposure
6. Normal renal and liver function

Exclusion criteria:

1. Poor growth associated with any acute or chronic medical condition such as renal disease or Turner's syndrome.
2. History of diabetes or malignancy
3. Use of glucocorticoids or medications known to affect the GH-IGF-1 axis within 6 months of study entry.