Fatty Acid Oxidation Disorders & Body Weight Regulation Grant

• ClinicalTrials.gov Identifier: NCT00654004
• Recruitment Status: Completed
• First Posted: April 7, 2008
• Results First Posted: April 22, 2013
• Last Update Posted: April 22, 2013
• Sponsor: Oregon Health and Science University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Oregon State University
• Information provided by (Responsible Party): Melanie B Gillingham, Oregon Health and Science University

Study Description

Brief Summary:

Several hormones involved in body weight regulation increase the subject's ability to burn fat for energy. The purpose of this study is to investigate how burning fat for energy may affect those hormones and body weight in children. The study will also determine if eating a diet higher in protein alters the amount of fat you burn and how these hormones control body weight.

Condition or disease
Trifunctional Protein Deficiency

Detailed Description:

A role for mitochondrial fatty acid oxidation in the peripheral signaling cascade of leptin, adiponectin and insulin has recently been proposed from animal studies but has not been investigated in humans. Children with trifunctional protein (TFP, including deficiency of long-chain hydroxyacyl-CoA dehydrogenase) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, inherited disorders of long-chain fatty acid ß-oxidation, lack an ability to oxidize fatty acids for energy. They have increased levels of body fat and circulating leptin and a high incidence of obesity. Current therapy for children with these disorders is based on frequent meals and consuming a low fat, very high carbohydrate diet. Despite treatment, exercise induced rhabdomyolysis is a common complication of TFP and VLCAD deficiency that frequently leads to exercise avoidance. The effects of these genetic defects on body composition and weight regulation have not been investigated. The contribution of fatty-acid oxidation during moderate intensity exercise in children has also not been reported.

Two groups of subjects were recruited: one group of subjects had a long-chain fatty acid oxidation disorder (n=13). The other group is a group of controls (n=16). We studied peripheral signals of body weight regulation, glucose tolerance, body composition, and exercise metabolism in subjects with a long-chain fatty acid oxidation disorder compared to normal controls.

Study Design

• Study Type: Observational
• Actual Enrollment: 26 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Fatty Acid Oxidation Disorders & Body Weight Regulation
• Study Start Date: April 2006
• Actual Primary Completion Date: September 2010
• Actual Study Completion Date: January 2011

Groups and Cohorts

Group/Cohort
Subjects; Subjects are patients with a long-chain fatty acid oxidation disorder including CPT2, VLCAD, TFP or LCHAD deficiency.
Controls; Subjects do not have a fatty acid oxidation disorder.

Outcome Measures

Primary Outcome Measures :

1. An Outcome of This Study is the Difference in Percent Body Fat (%BF) Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. [ Time Frame: Subjects will be compared to controls at one point in time. ]
   Body composition by DEXA was measured in subjects with a long-chain fatty acid oxidation disorder (n=13). Twelve age, sex and BMI matched controls and 4 heterozygotes for a long-chain fatty acid oxidation disorder were recruited who also completed body composition measures. The difference in body composition between subjects and age matched controls was compared by t-test.
2. An Outcome of This Study is the Difference in Glucose Tolerance Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Normal Controls. [ Time Frame: Subjects will be compared to controls at one point in time. ]

   Glucose tolerance was estimated by the Matsuda Index using glucose and insulin values from a standard oral glucose tolerance test. The Matsuda Index is calculated by the following formula: 10,000/ sq root of (fasting glucose mg/dl X fasting insulin in units/ml) X (mean glucose (mg/dl) X mean insulin (units/ml) and correlates with insulin sensitivity measured by the gold standard method of a hyperinsulinemic euglycemic clamp. Values of 2.5 or greater are considered insulin sensitive. Values of 2.4 or less are considered insulin resistance.

   The Matsuda Index of Insulin Sensitivity was measured in subjects with a long-chain fatty acid oxidation disorder (n=12). Twelve age, sex and BMI matched controls and 4 heterozygotes for a long-chain fatty acid oxidation disorder were recruited who also completed an oral glucose tolerance test. The difference in Mastuda Index between subjects and age matched controls was compared by t-test.

Secondary Outcome Measures :

1. The Difference in Plasma Adiponectin Levels Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test [ Time Frame: Fasting total adiponectin (ug/ml) ]
   Fasting total adiponectin levels in ug/ml were measured in both groups (subjects with a long-chain fatty acid oxidation disorder). The differences between groups were compared with a t-test
2. The Difference in Plasma Leptin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test [ Time Frame: Fasting leptin levels ng per kg of fat mass ]
   Fasting leptin in ng/kg fat mass were measured in both groups (subjects with a long-chain fatty acid oxidation disorder; controls). The differences between groups were compared with a t-test
3. The Difference in Plasma Insulin Between Subjects With a Long-chain Fatty Acid Oxidation Disorder and Matched Controls Was Compared by T-test [ Time Frame: Fasting insulin levels uUnits/ml ]
   Fasting insulin levels in uU/ml were measured in both groups. The differences between groups were compared with a t-test

Biospecimen Retention:   Samples Without DNA

Blood and urine samples. Body composition and energy expenditure data. MRI/MRS images.

Eligibility Criteria

• Ages Eligible for Study: 7 Years to 40 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Subjects were patients with a diagnosis of mitochondrial trifunctional protein, long-chain 3-hydroxyacylCoA dehydrogenase, very long-chain acylCoA dehydrogenase or carnitine palmitoyltransferase 2 deficency. They were recruited through advertisements on the FAO support website, or physician referral. Control subjects were from the greater Portland area. They were recruited via adverstisements at OHSU.

Criteria

Inclusion Criteria:

• confirmed diagnosis of TFP, LCHAD, CPT2 or VLCAD deficiency
• at least 7 years of age
• willingness to complete overnight admission
• generally healthy

Exclusion Criteria:

• inclusion in another research project that alters macronutrient intake
• diabetes, thyroid disease or other endocrine dysfunction that alters body composition.
• pregnancy
• anemia

Contacts and Locations

Locations

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

Sponsors and Collaborators

Oregon Health and Science University

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Oregon State University

Investigators

• Principal Investigator: Melanie B. Gillingham, PhD; Oregon Health and Science University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Behrend AM, Harding CO, Shoemaker JD, Matern D, Sahn DJ, Elliot DL, Gillingham MB. Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidation. Mol Genet Metab. 2012 Jan;105(1):110-5. doi: 10.1016/j.ymgme.2011.09.030. Epub 2011 Oct 1.

• Responsible Party: Melanie B Gillingham, Assistant Professor, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT00654004
• Other Study ID Numbers: DK71869; K01DK071869 ( U.S. NIH Grant/Contract )
• First Posted: April 7, 2008
• Results First Posted: April 22, 2013
• Last Update Posted: April 22, 2013
• Last Verified: April 2013

Keywords provided by Melanie B Gillingham, Oregon Health and Science University:

trifunctional; protein; deficiency; TFP; weight; regulation

Additional relevant MeSH terms:

Protein Deficiency; Body Weight; Deficiency Diseases; Malnutrition; Nutrition Disorders