Macronutrient Regulation of Ghrelin and Peptide YY

Obesity Clinical Trial

Official title:

Investigation of the Developmental, Nutritional and Hormonal Regulation of Ghrelin in Children With Prader-Willi Syndrome (PWS) and Children With Hypothalamic-Derived Obesity: Macronutrient Regulation Sub-study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02464514
• Other study ID #: 5028
• Secondary ID: 1K23RR021979
• Status: Completed
• Phase: N/A
• First received: June 1, 2015
• Last updated: August 6, 2015
• Start date: January 2004
• Est. completion date: December 2005

Study information

• Verified date: June 2015
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The hyperghrelinemia of children with PWS provides a unique model by which to explore the hormonal and metabolic effects of orexigenic hormones in normal and pathologic conditions. An important question to be addressed by this proposed research includes the macro-nutrient regulation of ghrelin and PYY in obese children and children with PWS. As ghrelin antagonists are considered potential future anti-obesity agents, it is essential to gain understanding of the developmental, nutritional and hormonal regulation of this important orexigenic hormone in children.

Description:

Obesity continues to be a prevalent health concern affecting every race of the American population. Studies show that obese children are likely to become obese adults. Also, recent studies report significant years of life lost due to the impact of being an obese adult . Thus, insights into the pathogenesis of childhood obesity and preventative measures are needed to combat the inevitable increase in worldwide incidence of obesity and its associated co-morbidities.

Ghrelin is a 28 amino acid acylated peptide which is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), a hypothalamic G-protein-coupled receptor. Enteroendocrine cells (X/A-like cells) of the stomach are the major site of ghrelin synthesis, although a minor proportion of ghrelin synthesis occurs in other sites such as the hypothalamus, pituitary, duodenum, jejunum and lung. Secreted in response to meals, ghrelin stimulates feeding through activation of anabolic neurons in the hypothalamic arcuate nucleus that co-express neuropeptide Y (NPY) and agouti-related protein (Agrp). Ghrelin relays its information from the GI tract to specific nuclei in the hypothalamus via the gastric afferent vagal nerve.

Studies in rodents support the premise that ghrelin is involved in energy balance. In humans, physiological levels of ghrelin influence energy homeostasis in humans.The rise in plasma ghrelin concentrations during fasting may play a role in meal initiation and body weight regulation.

Nearly all other forms of obesity are associated with low ghrelin levels. Paradoxically, researchers discovered that ghrelin levels in adults and children with PWS are 3-5 times higher than those in age- and BMI-matched controls. Hyperghrelinemia may thus play a causal role in the hyperphagia and obesity of PWS.

The hyperghrelinemia of children with PWS provides a unique model by which to explore the hormonal and metabolic effects of orexigenic hormones in normal and pathologic condtions. An important question to be addressed by this proposed research includes the macro-nutrient regulation of ghrelin in normal children and children with PWS. As ghrelin antagonists are considered potential future anti-obesity agents, it is essential to gain understanding of the developmental, nutritional and hormonal regulation of this important orexigenic hormone in children.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: December 2005
• Est. primary completion date: December 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years to 17 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of PWS confirmed by chromosome analysis (i.e. interstitial deletion of paternally-derived chromosome 15Q, uniparental maternal disomy or other chromosome 15 abnormalities) or normal control

2. Subjects with simple obesity

3. Ages 5 years to 17 years

4. Written informed consent and assent obtained and willingness to comply with the study schedule and procedures.

5. Free T4, TSH values in the normal range (either endogenous or with thyroxine replacement)

Exclusion Criteria:

1. Patients with any other clinically significant disease that would have an impact on body composition including diabetes mellitus, chronic inflammatory bowel disease, chronic severe liver or kidney disease or neurologic disorders

2. Concomitant use of an investigational drug in the past year

3. Patients with an active malignancy

4. Parent or legal guardian unable to provide informed consent.

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Obesity
• Prader Willi Syndrome
• Prader-Willi Syndrome

Intervention

Other:
• High carbohydrate meal
65% carbohydrate, 17% protein, and 18% fat
• High fat meal
58% fat, 17% protein, and 25% carbohydrate

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina

Sponsors (10)

Lead Sponsor	Collaborator
Duke University	Alberta Diabetes Institute, American Diabetes Association, Canadian Institutes of Health Research (CIHR), Duke Children's Miracle Network, Foundation for Prader-Willi Research (FPWR), National Center for Research Resources (NCRR), National Institutes of Health (NIH), Sarah W. Stedman Nutrition and Metabolism Center, Stollery Children's Hospital Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in ghrelin levels	The change in ghrelin levels will be measured before and after meal consumption in children with PWS, and healthy obese controls. Following an overnight 8 hour fast, subjects will be given either a high carbohydrate or high fat meal. Subjects will be allowed 25 minutes to consume everything on their food tray. Blood samples will be obtained before the meal (fasting) and every 30 minutes thereafter for 4 hours.	4 hours	No
Primary	Change in PYY concentrations	The change in PYY concentration levels will be measured before and after meal consumption in children with PWS, and healthy obese controls. Following an overnight 8 hour fast, subjects will be given either a high carbohydrate or high fat meal. Subjects will be allowed 25 minutes to consume everything on their food tray. Blood samples will be obtained before the meal (fasting) and every 30 minutes thereafter for 4 hours.	4 hours	No
Secondary	Fasting Insulin-like growth factor 1 (IGF-1) levels	Baseline Insulin-like growth factor 1 (IGF-1) levels will be measured fasting before the meal in children with PWS, and healthy obese controls	Baseline	No
Secondary	Neuropeptide Y (NPY)	Baseline Neuropeptide Y (NPY) levels will be measured fasting before the meal in children with PWS, and healthy obese controls	Baseline	No
Secondary	Gastric inhibitory polypeptide (GIP)	Baseline Gastric inhibitory polypeptide (GIP) levels will be measured fasting before the meal in children with PWS, and healthy obese controls	Baseline	No
Secondary	Glucagon-like peptide-1 (GLP-1)	Baseline Glucagon-like peptide-1 (GLP-1) levels will be measured fasting before the meal in children with PWS, and healthy obese controls	Baseline	No