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Determinants of Liver Fat Composition

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03211299
Recruitment Status : Completed
First Posted : July 7, 2017
Last Update Posted : June 4, 2018
Sponsor:
Collaborator:
Unilever R&D
Information provided by (Responsible Party):
Maastricht University Medical Center

Brief Summary:
Excessive fat in the liver, in absence of high alcohol consumption, is diagnosed as non-alcoholic fatty liver (NAFL). NAFL prevalence is as high as 50-70% in obese people and is associated with impairments in metabolic health, e.g. insulin resistance. Not only the amount, but also the composition of the fat stored in the liver appears to be linked to health outcome measures, such as insulin resistance, but this evidence comes mainly from animal studies. Since fat composition has been linked to health outcome measures, it is important to understand what determines the fatty acid composition of liver fat. De novo lipogenesis (DNL) and adipose tissue fat composition are factors that could determine liver fat composition. Since the end product of DNL are saturated fatty acids and as the majority of fatty acids in the liver originate from adipose tissue, both may influence hepatic fatty acid composition profoundly. Here, our primary hypothesis is that DNL is associated with the relative amount of saturated fatty acids in the liver in overweight/obese humans differing in liver fat content. Furthermore, we hypothesise that adipose tissue fat composition is associated with liver fat composition and that liver fat composition is associated with liver, muscle and whole body insulin sensitivity in overweight/obese humans differing in liver fat content. To this end, liver fat composition, adipose tissue fat composition, DNL and insulin sensitivity will be measured in overweight/obese participants differing in liver content.

Condition or disease
Fatty Liver, Nonalcoholic Insulin Sensitivity

Detailed Description:

Rationale: Excessive fat in the liver, in absence of high alcohol consumption, is diagnosed as nonalcoholic fatty liver (NAFL). NAFL prevalence is as high as 50-70% in obese people and is associated with impairments in metabolic health, e.g. insulin resistance. Not only the amount, but also the composition of the fat stored in the liver appears to be linked to health outcome measures, such as insulin resistance, but this evidence comes mainly from animal studies. Since fat composition has been linked to health outcome measures, it is important to understand what determines the fatty acid composition of liver fat. De novo lipogenesis (DNL) and adipose tissue fat composition are factors that could determine liver fat composition. Since the end product of DNL are saturated fatty acids and as the majority of fatty acids in the liver originate from adipose tissue, both may influence hepatic fatty acid composition profoundly. Up to now, associations between hepatic fatty acid composition, DNL and adipose tissue fatty acid composition have never been determined in the same study.

Objective: The primary objective of this study is to determine the association between DNL and hepatic %SFA in overweight/obese subjects differing in liver fat content. The secondary objectives are to determine the association between adipose tissue fat composition and liver fat composition and to determine the association between liver fat composition and whole body, liver and muscle insulin sensitivity.

Study design: This is a cross-sectional observational study. For this study a design of 3 groups with different amounts of liver fat are included, in order to create a study population with a continuum in liver fat content.

Study population: Twenty-two healthy overweight/obese males and females, aged between 45-70 years and BMI between 27-35 kg/m2 will participate in the whole study. To create a continuum in liver fat content, eight subjects with liver fat content lower than 5% and 14 subjects with liver fat content higher than 5%, of which at least seven subjects have a liver fat content of at least 15%, will be included. To be able to include enough people in each group, around 31 participants will be included in total. A part of the participants will stop participating in the study after determination of liver fat content (in case the liver fat content does not match the groups).

Main study parameters/endpoints: The primary study parameters are %SFA in the liver and DNL. %SFA in the liver will be determined using MRS and DNL will be determined by applying stable isotope techniques. The secondary study parameters are hepatic fat composition, measured as %MUFA and %PUFA in addition to %SFA using MRS, adipose tissue fat composition, determined using MRS and biopsies, and insulin sensitivity, measured by a hyperinsulinemic euglycemic 2- step clamp.

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Study Type : Observational
Actual Enrollment : 19 participants
Observational Model: Other
Time Perspective: Cross-Sectional
Official Title: Determinants of Liver Fat Composition in Overweight and Obese Humans
Actual Study Start Date : August 15, 2017
Actual Primary Completion Date : May 5, 2018
Actual Study Completion Date : May 17, 2018


Group/Cohort
IHL <5%
overweight and obese humans with a liver fat percentage <5%
IHL 5-10%
overweight and obese humans with a liver fat percentage 5-15%
IHL >15%
overweight and obese humans with a liver fat percentage >15%



Primary Outcome Measures :
  1. %SFA in the liver [ Time Frame: 20 minutes ]
    expressed as relative amount of SFA to the total amount of fatty acids (determined by magnetic resonance spectroscopy)

  2. DNL [ Time Frame: 16 hours ]
    expressed as percentage of palmitate in VLDL-TG originating from DNL (determined by use of deuterium water)


Secondary Outcome Measures :
  1. Liver fat composition [ Time Frame: 20 minutes ]
    expressed as relative amount of MUFA and PUFA to the total amount of fatty acids, in addition to %SFA (determined by magnetic resonance spectroscopy)

  2. Adipose tissue fat composition [ Time Frame: 20 minutes ]
    expressed as relative amount of SFA, MUFA and PUFA to the total amount of fatty acids (determined by magnetic resonance spectroscopy and from subcutaneous adipose tissue biopsy)

  3. Adipose tissue fat composition [ Time Frame: 15 minutes ]
    expressed as relative amount of linoleic acid, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to the total amount of fatty acids (determined from subcutaneous adipose tissue biopsy)

  4. Hepatic insulin sensitivity [ Time Frame: 8.5 hours ]
    expressed as % suppression of endogenous glucose production (EGP)(determined by hyperinsulinemic euglycemic clamp).

  5. Muscle insulin sensitivity [ Time Frame: 15 minutes ]
    expressed as determinants/markers for muscle insulin sensitivity in muscle biopsy (oxphos, GLUT4, intramyocellular lipids (IMCL).

  6. peripheral insulin sensitivity [ Time Frame: 8.5 hours ]
    expressed as rate of disappearance (Rd) in μmol/kg/min (determined by hyperinsulinemic euglycemic clamp).

  7. whole body insulin sensitivity [ Time Frame: 8.5 hours ]
    expressed as glucose infusion rate (GIR) in μmol/kg/min (determined by hyperinsulinemic euglycemic clamp).


Other Outcome Measures:
  1. Intrahepatic fat accumulation [ Time Frame: 10 minutes ]
    expressed as % (determined by magnetic resonance spectroscopy)

  2. body composition [ Time Frame: 15 minutes ]
    expressed as fat mass (%) and fat-free mass (%) (determined by BodPod)

  3. abdominal visceral adipose tissue and abdominal subcutaneous adipose tissue [ Time Frame: 10 minutes ]
    expressed as % (determined by magnetic resonance spectroscopy)



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Ages Eligible for Study:   45 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Twenty-two healthy overweight/obese males and females, aged between 45-70 years and BMI between 27-35 kg/m2 will participate in the whole study. To create a continuum in liver fat content, eight subjects with liver fat content lower than 5% and 14 subjects with liver fat content higher than 5% (NAFL) will be included. At least seven volunteers with NAFL will have severely elevated hepatic fat content (liver fat percentage ≥ 15%).
Criteria

Inclusion Criteria:

  • Signed informed consent
  • Caucasian (people will be excluded when having a 50% or a more then 50% racial African/Asian background)
  • Male or postmenopausal female
  • Aged 45-70 years at start of the study
  • Body mass index (BMI) 27 - 35 kg/m2
  • Stable dietary habits (no weight loss or gain >3kg in the past 3 months)
  • Sedentary lifestyle (not more than 2 hours of sports per week)

Exclusion Criteria:

  • Type 2 diabetes
  • Active diseases (cardiovascular, diabetes, liver, kidney, cancer or other)
  • Contra-indication for MRI (which can be found in appendix I)
  • Alcohol consumption of >2 servings per day
  • Smoking >5 cigarettes per day
  • Use of anti-coagulants

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03211299


Locations
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Netherlands
Maastricht University Medical Center
Maastricht, Limburg, Netherlands, 6229 ER
Sponsors and Collaborators
Maastricht University Medical Center
Unilever R&D
Investigators
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Principal Investigator: Vera B Schrauwen, Dr Maastricht University Medical Center
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Responsible Party: Maastricht University Medical Center
ClinicalTrials.gov Identifier: NCT03211299    
Other Study ID Numbers: NL60263.068.16
First Posted: July 7, 2017    Key Record Dates
Last Update Posted: June 4, 2018
Last Verified: June 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Insulin Resistance
Liver Diseases
Digestive System Diseases
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases