Insulin Resistance in Nonalcoholic Fatty Liver Disease: A Case Control Study

July 10, 2017 updated by: Duke University
We hypothesize that insulin resistance is characteristic of nonalcoholic fatty liver disease as compared to age, gender, non-diabetic BMI-matched control subjects, both healthy and those with non-cirrhotic, non-steatotic liver disease.

Study Overview

Status

Terminated

Conditions

Detailed Description

Purpose of the study:

To date, no case control study evaluating insulin resistance (IR) in nonalcoholic fatty liver disease (NALFD) has been published. We hypothesize that IR is characteristic of NAFLD as compared to age, gender, non-diabetic BMI-matched control subjects, both healthy and those with non-cirrhotic, non-steatotic liver disease. The following aims test this central hypothesis:

Specific Aim 1: Measure IR and insulin clearance using intravenous glucose tolerance testing and Bergman's Minimal Modeling in patients with NAFLD as compared to matched controls (healthy and those with non-steatotic hepatitis). This aim tests the postulate that IR is necessary for the development of hepatic steatosis as compared to healthy (non-steatotic livers). It will also test the postulate that IR is not present as a confounding factor (impaired hepatic clearance) in NAFLD as compared to those with non-steatotic forms of hepatitis.

Specific Aim 2: Determine if IR is associated with altered parameters of lipid metabolism as compared to matched controls. This aim addresses whether IR (if present) is associated with abnormal lipid parameters in NAFLD or can be observed irrespective of the presence of hepatic steatosis.

Specific Aim 3: Measure the differential effects of IR and lipid metabolism on peripheral mononuclear cell (PBMC) inflammatory response and the associated hepatocyte mitochondrial ultrastructure and measures of oxidative stress. Since increased oxidative stress and bioenergetic failure have been associated with hepatic steatosis, this aim will address whether IR and/or steatosis results in impaired inflammatory response and increased oxidative stress as compared to controls. Changes in innate immune response will be determined by measuring inflammatory indices thought to correlate with obesity, IR, and/or chronic hepatitis: 1) interleukins (IL-2, IL-4, IL-6, IL-10, IL-12, IL-18) 2) C-reactive protein, 3) TNF-a and TGF-B 4) IFN-A & IFN-g, and 5) adiponectin. Changes in oxidative stress will be determined by measuring key indices of oxidative stress and damage. These include, a) reduced and oxidized glutathione (GSH and GSSG); oxidation/reduction status), b) malondialdehyde (MDA;lipid peroxidation), c) nitrotyrosine (NO damage), and d) 8OHdG and 8OHG (DNA damage).

Background and significance:

Obesity, diabetes, hypertriglyceridemia, hypertension, and coronary heart disease constitute a phenotype common to individuals with either the IR syndrome or NAFLD1-12. Furthermore, the hepatic steatosis, fibrosis, and cirrhosis characteristic of NAFLD are also frequent histologic findings in patients with IR 3-7. Together, these data beg the question whether NAFLD and IR are causally associated. Support for this notion derives from recent observations that IR may be a strong, independent predictor of NAFLD, even in the absence of glucose intolerance 13. Moreover, since NAFLD has been reported to occur in lean subjects (BMI greater than 25) with normoglycemia 14, 15, it is reasonable to postulate that NAFLD may be an early manifestation and a consequence of IR. Increased oxidative stress is an important pathogenic mechanism of obesity-associated metabolic syndrome 16. Fat accumulation correlated with systemic oxidative stress in humans and mice. However, increase oxidative stress as an instigator of the metabolic syndrome in patients with NAFLD as compared to controls has not yet been investigated. Furthermore, impaired cytokine medicated inflammatory response has been shown to correlate with body mass index across the broad range of obesity and may mediate hepatic steatosis and/or lead to mitochondrial dysfunction in hepatocytes 17, 18. Discerning whether NAFLD is attributable to increased oxidative stress and/or abnormalities in innate immune response would be imperative in identifying potentially useful therapeutic targets for obesity-associated liver disease.

Study Type

Observational

Enrollment (Actual)

29

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Liver Clinic, Liver Transplant Clinic, Weight Loss Surgery Clinic

Description

Inclusion Criteria:

  • Biochemical and liver histologic features to confirm the presence of a healthy liver, fatty liver, and/or non-fatty liver with inflammation due to another etiology besides NAFLD.

Exclusion Criteria:

  • > 20 grams of alcohol/day
  • Impaired oral glucose tolerance test
  • Clinical or histologic evidence of cirrhosis (stage 5-6 fibrosis) or portal hypertension.
  • Chronic hepatitis C infection
  • Known diabetes mellitus or need for insulin-sensitizing agents and/or insulin therapy.
  • Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort
1
Subjects with NAFLD
2
Subjects without liver disease
3
Subjects with non-steatotic hepatitis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Measure Insulin Resistance (IR) and clearance its effects on lipid metabolism, inflammatory response, and oxidative stress using intravenous glucose tolerance testing in patients with NAFLD as compared to matched controls.
Time Frame: 36 months
36 months
Determine if IR is associated with altered parameters of lipid metabolism as compared to matched controls
Time Frame: 36 months
36 months
Measure the differential effects of IR and lipid metabolism on peripheral mononuclear cell (PBMC) inflammatory response and the associated hepatocyte mitochondrial ultrastructure and measures of oxidative stress.
Time Frame: 36 Months
36 Months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Duke University

Collaborators

University of Florida

Investigators

  • Principal Investigator: Manal F Abdelmalek, MD., MPH, faculty member

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2007

Primary Completion (Actual)

March 29, 2013

Study Completion (Actual)

April 13, 2017

Study Registration Dates

First Submitted

March 12, 2008

First Submitted That Met QC Criteria

March 17, 2008

First Posted (Estimate)

March 18, 2008

Study Record Updates

Last Update Posted (Actual)

July 11, 2017

Last Update Submitted That Met QC Criteria

July 10, 2017

Last Verified

September 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00006742
  • NIH K23 Award
  • 8592 (Other Identifier: Duke legacy protocol number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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