Hepatic De Novo Lipogenesis (DNL)in the Pathogenesis of Hepatic Steatosis in Obese Youth
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Purpose
Nonalcoholic Fatty Liver Disease (NAFLD) is becoming the most common cause of liver disease in pediatrics, but little is known about its pathophysiology in children. While studies in obese adults with hepatic steatosis have described an increased hepatic de novo lipogenesis (DNL) depending on the diet, there are no studies exploring the mechanisms by which excess hepatic triglycerides increases in obese youths, thus explaining the accompanying dyslipidemia and the metabolic syndrome. The central hypothesis of this study is that hepatic conversion of carbohydrates to lipid (DNL) is enhanced and associated with accumulation of excess liver fat, dyslipidemia and hepatic insulin resistance in obese youths with hepatic steatosis. The overall goal is to examine whether hepatic DNL is increased in obese youths with steatosis compared to matched controls without steatosis.
Hypotheses: Hepatic conversion of carbohydrates to lipid (DNL) is enhanced and is associated with accumulation of excess liver fat, dyslipidemia and hepatic insulin resistance in obese youths with hepatic steatosis.
| Condition |
|---|
|
Hepatic Steatosis Fatty Liver |
| Study Type: | Observational |
| Study Design: | Observational Model: Case Control Time Perspective: Prospective |
| Official Title: | The Role of Hepatic De Novo Lipogenesis (DNL) in the Pathogenesis of Hepatic Steatosis in Obese Children and Adolescents |
- de novo lipogenesis response to high carbohydrate meal in obese kids with fatty liver [ Time Frame: Study visit 3 ] [ Designated as safety issue: No ]
- de novo lipogenesis response to high carbohydrate meal in obese kids without fatty liver [ Time Frame: Study visit 3 ] [ Designated as safety issue: No ]
Biospecimen Retention: Samples With DNA
Serum
| Estimated Enrollment: | 60 |
| Study Start Date: | December 2010 |
| Estimated Study Completion Date: | August 2013 |
| Estimated Primary Completion Date: | June 2013 (Final data collection date for primary outcome measure) |
| Groups/Cohorts |
|---|
| Fatty liver |
| Non Fatty liver |
Detailed Description:
In this study obese youths (12-18 years) will undergo MRI (magnetic resonance imaging) measurement of liver lipid content to determine hepatic fat content. They will undergo a sugary drink (75 grams of glucose and 25 grams of fructose) challenge and Hepatic de novo lipogenesis will be determined as the incorporation of deuterium, from deuterium labeled water (D2O), into plasma triglycerides. Subjects will undergo a 6 hours study assessing de novo lipogenesis, an oral glucose tolerance test, dual energy x-ray absorptiometry, magnetic resonance imaging, and Euglycemic-Hyperinsulinemic Clamp.
Eligibility| Ages Eligible for Study: | 12 Years to 18 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
| Sampling Method: | Non-Probability Sample |
The majority of the research subjects will be recruited from the Yale Pediatric Obesity Clinic and the Endocrine Clinic. Following the oral glucose tolerance test (OGTT):normal glucose tolerant if plasma glucose at two hours is <140 mg/dl and impaired glucose tolerant if plasma glucose is ≥140 mg/dl. All subjects must be in good general health, have a normal medical history and physical exam, and have no endocrinopathies or other diseases that might affect glucose metabolism. They will not be on any medications that are known to alter glucose or insulin metabolism or certain psychiatric medications. Subjects determined to be eligible will receive a MRI to determine Hepatic Fat Content. Subjects will agree to genetic testing to determine genotype.
Inclusion Criteria:
Cases will meet the following criteria:
- Age between 12 and 18 years
- BMI higher than 85th percentile
- Hepatic fat fraction (the amount of fat into the liver) greater or equal than 5.5%
- Absence of any endocrinopathy
- Absence of any therapy with medication known to alter glucose metabolism
Controls will meet the following criteria:
- Age between 12 and 18 years
- BMI higher than 85th percentile
- Hepatic fat fraction (the amount of fat into the liver) lower than 5.5%
- Absence of any endocrinopathy
- Absence of any therapy with medication known to alter glucose metabolism
Exclusion Criteria:
BMI under the 85th percentile
- Hepatic fat fraction (the amount of fat into the liver) less than 5.5%
- Absence of any endocrinopathy
- Any therapy with medication known to alter glucose metabolism
Controls will meet the following criteria:
- BMI under the 85th percentile
- Hepatic fat fraction (the amount of fat into the liver) greater than or equal to 5.5%
- Any endocrinopathy
- Any therapy with medication known to alter glucose metabolism
Contacts and Locations| Contact: Bridget Pierpont, M.A. | 203-785-2942 | bridget.pierpont@yale.edu |
| United States, Connecticut | |
| Yale University | Recruiting |
| New Haven, Connecticut, United States, 06510 | |
| Contact: Bridget Pierpont, M.A. 203-785-2942 bridget.pierpont@yale.edu | |
| Principal Investigator: Nicola Santoro, M.D./Ph.D | |
| Principal Investigator: | Sonia Caprio, M.D. | Yale University |
| Principal Investigator: | Nicola Santoro, M.D./Ph.D, | Yale University |
More Information
No publications provided
| Responsible Party: | Sonia Caprio, Professor of Pediatrics, Yale University |
| ClinicalTrials.gov Identifier: | NCT01725035 History of Changes |
| Other Study ID Numbers: | 1008007192, 11CRP5620013 |
| Study First Received: | October 30, 2012 |
| Last Updated: | March 7, 2013 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Yale University:
|
De Novo Lipogenesis Fatty Liver Hepatic Steatosis Gene variants |
Additional relevant MeSH terms:
|
Fatty Liver Liver Diseases Digestive System Diseases |
ClinicalTrials.gov processed this record on June 18, 2013