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

This study is currently recruiting participants.
Verified August 2013 by Duke University
Sponsor:
Collaborator:
University of Florida
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00637520
First received: March 12, 2008
Last updated: August 14, 2013
Last verified: August 2013
  Purpose

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.


Condition
Insulin Resistance
Nonalcoholic Fatty Liver Disease

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional
Official Title: Insulin Resistance in Nonalcoholic Fatty Liver Disease: A Case Control Study

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Determine if IR is associated with altered parameters of lipid metabolism as compared to matched controls [ Time Frame: 36 months ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Frozen tissue, serum, whole blood, urine


Estimated Enrollment: 80
Study Start Date: July 2007
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Groups/Cohorts
1
Subjects with NAFLD
2
Subjects without liver disease
3
Subjects with non-steatotic hepatitis

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Liver Clinic, Liver Transplant Clinic, Weight Loss Surgery Clinic

Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00637520

Contacts
Contact: Christopher Kigongo, MB,ChB. MPH (919) 668-6579 Christopher.Kigongo@duke.edu
Contact: Melissa Wagner, CCRC (919) 684-4798 melissa.wagner@duke.edu

Locations
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Principal Investigator: Manal F Abdelmalek, MD, MPH         
Sponsors and Collaborators
Duke University
University of Florida
Investigators
Principal Investigator: Manal F Abdelmalek, MD., MPH Faculty Member
  More Information

Publications:

Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00637520     History of Changes
Other Study ID Numbers: Pro00006742 (8592), NIH K23 Award
Study First Received: March 12, 2008
Last Updated: August 14, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Duke University:
Nonalcoholic Fatty Liver Disease
Insulin Resistance
Lipid Metabolism

Additional relevant MeSH terms:
Insulin Resistance
Fatty Liver
Liver Diseases
Digestive System Diseases
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 22, 2014