About this trial
Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide and affects nearly 40% of obese youth and up to 10% of the general pediatric population. Some features of NAFLD are similar in children and adults, yet fibrosis and inflammation are more common in the portal zone and occur earlier in pediatric NAFLD patients than adults. This portends a rapid progression to end-stage liver disease in early adulthood. For the majority of children with NAFLD, mechanisms driving the origin and rapid progression of disease remain unknown. Thus, there is a critical, unmet need to study the specific underlying patterns of metabolic and molecular changes in the liver underlying the development and progression unique to children with NAFLD.
This proposal will test the hypotheses that children with NAFLD have excess glucose and lipid produced by the liver, that those events are regulated by specific variations in the amount and location of RNAs and proteins in liver, and that the concentration of specific micro-RNAs in the blood can be used as a biomarker for NAFLD in pediatric patients.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
Age: All participants must be 10.0 to 20.9 years old at the time of enrollment.
Sex: Male and Female participants are eligible.
Race/Ethnicity: Participants of all racial/ethnic identities will be recruited.
Body mass index (BMI): Participants must be either in the normal weight (NW control group) or obese [Ob control, nonalcoholic fatty liver disease (NALFD) groups] range for BMI percentile. BMI percentile will be calculated from age- and sex-specific growth charts for children.
Disqualifiers
Chronic illness: Participants will not be able to participate if they have conditions that are likely to affect metabolic variables (either directly or due to required medications) or result in them being unable to complete the required tests. Such conditions could include, but are not limited to, untreated hypothyroidism or other endocrine disorders, rheumatoid arthritis requiring steroids or limiting mobility, cardiovascular disease, stroke, or cardiac failure, neurological disorders such as multiple sclerosis, cancer, liver diseases other than NAFLD (e.g., Wilson's disease), other organ disorders, or orthopedic conditions that limit physical activity.
Acute illness: Participants will not be able to participate if they develop acute conditions that are likely to affect metabolic outcomes (either directly or due to required medications) or result in them being unable to participate; e.g., respiratory illness, infectious disease, fever, accident resulting in bone fractures, myocardial infarction, major depression. If such conditions resolve and there are no longer risks or likelihood of adverse effect on the study outcomes, participants may be rescheduled for testing.
Medications and nutritional supplements: Medications, vitamins, or supplements that have known effects on the primary outcomes will be cause for exclusion. Examples include weight loss medications, glucocorticoids, or experimental medications used to correct a metabolic or hepatic condition. Medications used to control asthma, allergies, anxiety, depression, attention deficit disorder, menstrual cycle, hypothyroidism, gastric reflux, hypertension, and sleep will be allowed. Participants who are taking medications for treatment of acute illness or conditions such as cold, flu, injury, or infection will be rescheduled after they complete their treatment course.
Pregnancy: Evidence of pregnancy or intent to become pregnant during the study is cause for exclusion.
Trial design
Parallel
Treatments tested in this trial
Oral sugar tolerance test
Other interventionMeasurement of glucose and insulin for calculation of insulin sensitivity
De novo lipogenesis test
Other interventionOral consumption of deuterated water to measure incorporation of label into lipids
Gluconeogenesis test
Other interventionOral consumption of 13C-labeled glycerol to measure incorporation into glucose
Treatment groups
Trial outcomes
Primary outcomes
De novo lipogenesis
Measurement of the rate of newly synthesized triglycerides in plasma using deuterated water
Gluconeogenesis
Measurement of the rate newly synthesized glucose in circulation using labeled glycerol and deuterated water
Serum microRNA
Abundance of microRNAs in serum using a broad profiling platform and real-time quantitative polymerase chain reaction tests for confirming individual miRNAs
Abundance of liver collagen
Abundance of collagen in liver biopsy sections, using Second Harmonic Generation microscopy
Secondary outcomes
Targets of microRNA-122
Transcripts bound to microRNA-122, measured using high-throughput sequencing of cross- linked immunoprecipitates (HITS-CLIP)
Liver transcriptomics
Spatial distribution of messenger RNAs in liver biopsies
Other outcomes
Blood pressure
Brachial and central blood pressures
Arterial stiffness
Measured as carotid-femoral pulse wave velocity
Body composition
Whole body and regional lean and fat mass, measure with dual energy X-ray absorptiometry
Cardiorespiratory fitness
Peak oxygen consumption during bicycle ergometry test to volitional fatigue
Sponsors and contacts
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University of Oklahoma
Lead sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator