Hepatic De Novo Lipogenesis (DNL)in the Pathogenesis of Hepatic Steatosis in Obese Youth (DNL)

The Role of Hepatic De Novo Lipogenesis (DNL) in the Pathogenesis of Hepatic Steatosis in Obese Children and Adolescents

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.

Study Overview

• Status: Completed
• Conditions: Fatty Liver; Hepatic Steatosis

Detailed Description

In this study obese youths, adolescents and young adults (12-30 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.

This study record has been re-opened in 2019 and updated to reflect any changes having remained open since its inception with the Yale University IRB and also having obtained additional funding though NIDDK.

• Study Type: Observational
• Enrollment (Actual): 60

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 28 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

Inclusion Criteria:

• Cases will meet the following criteria:

  • BMI higher than 75th 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:

• BMI higher than 75th 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
• Absence of any therapy with medication known to alter glucose metabolism

Exclusion Criteria:

• BMI under the 75th 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 75th 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Fatty liver
Non Fatty liver

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
de novo lipogenesis response to high carbohydrate meal in obese kids with fatty liver	Study visit 3

Secondary Outcome Measures

Outcome Measure	Time Frame
de novo lipogenesis response to high carbohydrate meal in obese kids without fatty liver	Study visit 3

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); American Heart Association
• Investigators: Principal Investigator: Sonia Caprio, M.D., Yale University; Principal Investigator: Nicola Santoro, M.D./Ph.D,, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2010
• Primary Completion (Actual): August 10, 2022
• Study Completion (Actual): August 10, 2022

Study Registration Dates

• First Submitted: October 30, 2012
• First Submitted That Met QC Criteria: November 7, 2012
• First Posted (Estimated): November 12, 2012

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Hepatic Steatosis; Fatty Liver; De Novo Lipogenesis; Gene variants
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver
• Other Study ID Numbers: 1008007192; 11CRP5620013 (Other Grant/Funding Number: American Heart Association); 1R01DK114504-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No