- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00252499
Insulin Resistance in Non-alcoholic Fatty Liver Disease
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
NAFLD and nonalcoholic steatohepatitis (NASH) are common liver disorders that are strongly associated with obesity, type 2 diabetes and dyslipidemia. The underlying pathophysiology of fatty infiltration of the liver is thought to be related to insulin resistance, which is an almost universal finding in patients with NAFLD. It is also possible that fat infiltration and inflammation in the liver may impair insulin sensitivity, either locally in the liver, or peripherally via the actions of inflammatory cytokines. We hypothesize that insulin resistance is a major causal factor leading to fat deposition in the liver and NAFLD, and thus interventions aimed at improving insulin sensitivity will result in a reduction of hepatic inflammation and steatosis.
Specific Aim 1: To determine in a cross-sectional study whether NAFLD is associated with altered peripheral and hepatic insulin sensitivity and to study their relationships with hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, -cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with rosiglitazone, an insulin sensitizer, or fenofibrate, a triglyceride lowering agent, will improve both hepatic as well as peripheral insulin sensitivity and thereby improve hepatic steatosis and inflammation in subjects with NAFLD.
The results of the proposed study will have important implications for our understanding of the mechanisms underlying insulin resistance and abnormalities in lipid and glucose metabolism in subjects with NAFLD and for the design of future studies aimed at the prevention and treatment of this condition.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Washington
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Seattle, Washington, United States, 98108
- VA Puget Sound Health Care System, Seattle
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Age 18-80 years old Controls:
- otherwise healthy Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated ALT and fatty liver by CT or ultrasound
- Able to comply with taking 3 pills a day for 6 months and follow-up safety visits
Exclusion Criteria:
Controls:
- history or evidence of hepatic steatosis
Cases:
- Cirrhosis on liver biopsy or by clinical exam or fibrosis score
- Causes of liver dysfunction other than NASH
Use of medications associated with hepatic steatosis:
- glucocorticoids
- estrogens
- tamoxifen
- amiodarone
- accutane
- sertraline
Use of medications that cause insulin resistance:
- niacin
- glucocorticoids
- anti-HIV drugs or atypical antipsychotics
- Use of lipid-lowering medications except stable dose statin
Use of anti-NASH drugs such as:
- ursodeoxycholic acid
- betaine milk thistle
- Use of coumadin
- Use of nitrates
Significant alcohol consumption:
- Average >20 grams/day
In subjects with diabetes
- a HbA1c >7.5% or use of insulin
- metformin
- rosiglitazone or pioglitazone
Liver transaminases:
- Cases: ALT >5x upper limit of normal
- Controls: ALT or AST above the normal range
- Iron saturation >50%
- Creatinine >1.5 mg/dl for men and >1.4 mg/dl for women
- Hematocrit <33%
- Pregnancy or lactation
- Significant weight loss within the past 6 months for controls, or since the liver biopsy for case subjects, history of significant coronary artery disease or congestive heart failure
- Retinopathy
Study Plan
How is the study designed?
Design Details
- Primary Purpose: BASIC_SCIENCE
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: TRIPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
PLACEBO_COMPARATOR: Placebo Arm
matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
|
placebo tablets that are matched to look like rosiglitazone
placebo matched to look like fenofibrate tablets
|
EXPERIMENTAL: Rosiglitazone Arm
rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
|
placebo matched to look like fenofibrate tablets
PPAR-gamma agonist, insulin sensitizer
|
EXPERIMENTAL: Fenofibrate Arm
micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid
|
placebo tablets that are matched to look like rosiglitazone
PPAR-alpha agonist, reduces triglycerides
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Liver/Spleen Ratio at 6 Months
Time Frame: 6 months
|
Liver fat was estimated by non-contrast CT scan measuring the density ratio between the liver and spleen by Hounsfield units (liver/spleen ratio), which has been previously correlated with liver fat quantification by magnetic resonance spectroscopy.Ten separate measurements equally distributed throughout the liver and spleen were obtained and the Hounsfield units averaged.
In subjects with more than one slice through the liver and spleen, the values for all slices were averaged.
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months
Time Frame: 6 months
|
6 months
|
|
Change in the Liver Spleen Ratio by CT Scan From Baseline to 6 Months as a Measure of Fat in the Liver
Time Frame: 6 months
|
6 months
|
|
Change in Peripheral Insulin Sensitivity From Baseline to 6 Months
Time Frame: 6 months
|
A two-step stable isotope labeled, hyperinsulinemic-euglycemic clamp procedure was performed with a low dose insulin infusion (20 mU/m2/min) for 3 hours followed by a primed high dose insulin infusion (160 mU/m2/min x 5 minutes then 80 mU/m2/min) for two hours.
D20 was infused and adjusted to maintain the blood glucose at 90 mg/dl.
Samples for glucose, insulin and 6,6 2d glucose were drawn every 15 minutes during the final half hour of the basal, low dose and high dose insulin periods.
Whole body insulin sensitivity was calculated as the rate of glucose disposal (Rd)/lean body mass during the high dose insulin infusion.
|
6 months
|
Changes in Intra-abdominal Fat Area From Baseline to 6 Months
Time Frame: 6 months
|
Unenhanced CT scan images were obtained on a General Electric Discovery HD750 CT scanner.
Intra-abdominal (IAF) areas were measured at the top of the iliac crest and quantified using the Tomovision program (SliceOMatic V4.3) by one trained technologist.
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6 months
|
Change in Hepatic Insulin Sensitivity From Baseline to 6 Months
Time Frame: 6 months
|
Hepatic insulin sensitivity was determined as the percent suppression of endogenous glucose production (EGP) at the end of the low dose insulin clamp.
|
6 months
|
Collaborators and Investigators
Investigators
- Principal Investigator: Kristina Marie Utzschneider, MD, VA Puget Sound Health Care System, Seattle
Publications and helpful links
General Publications
- Utzschneider KM, Largajolli A, Bertoldo A, Marcovina S, Nelson JE, Yeh MM, Kowdley KV, Kahn SE. Serum ferritin is associated with non-alcoholic fatty liver disease and decreased Beta-cell function in non-diabetic men and women. J Diabetes Complications. 2014 Mar-Apr;28(2):177-84. doi: 10.1016/j.jdiacomp.2013.11.007. Epub 2013 Nov 26.
- Kratz M, Marcovina S, Nelson JE, Yeh MM, Kowdley KV, Callahan HS, Song X, Di C, Utzschneider KM. Dairy fat intake is associated with glucose tolerance, hepatic and systemic insulin sensitivity, and liver fat but not beta-cell function in humans. Am J Clin Nutr. 2014 Jun;99(6):1385-96. doi: 10.3945/ajcn.113.075457. Epub 2014 Apr 16.
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Glucose Metabolism Disorders
- Metabolic Diseases
- Hyperinsulinism
- Liver Diseases
- Fatty Liver
- Insulin Resistance
- Non-alcoholic Fatty Liver Disease
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antimetabolites
- Hypolipidemic Agents
- Lipid Regulating Agents
- Rosiglitazone
- Fenofibrate
Other Study ID Numbers
- CDA-2-044-08S
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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