Insulin Resistance in Non-alcoholic Fatty Liver Disease
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| ClinicalTrials.gov Identifier: NCT01289639 |
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Recruitment Status :
Terminated
(Low recruitment in intervention study. Baseline data published.)
First Posted : February 4, 2011
Results First Posted : October 20, 2014
Last Update Posted : August 17, 2017
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Fatty Liver | Drug: fenofibrate Drug: pioglitazone Drug: placebo | Not Applicable |
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, beta-cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with pioglitazone, 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 : | Interventional (Clinical Trial) |
| Actual Enrollment : | 11 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Basic Science |
| Official Title: | Insulin Resistance in Non-alcoholic Fatty Liver Disease (Protocol Drug Change From Project Career Development Award (CDA)-2-044-08S) |
| Study Start Date : | October 2005 |
| Actual Primary Completion Date : | August 2013 |
| Actual Study Completion Date : | August 2014 |
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Placebo
matching placebo 1 po qd
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Drug: placebo
placebo 1 capsule po qd |
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Experimental: Fenofibrate
micronized fenofibrate 200 mg 1 po qd
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Drug: fenofibrate
micronized fenofibrate 200 mg 1 po qd
Other Name: micronized fenofibrate |
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Experimental: Pioglitazone
pioglitazone 30 mg po qd
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Drug: pioglitazone
pioglitazone 30 mg po qd
Other Name: Actos |
- Liver/Spleen Ratio Measured as the Ratio in Hounsfield Units Between the Liver and the Spleen on Computed Tomography (CT) Scan [ Time Frame: 6 months ]
- Change in Alanine Aminotransferase (ALT) Levels [ Time Frame: 0-6 months ]
- Change in Liver/Spleen Ratio Measure by the Density Ratio in Hounsfield Units Between the Liver and the Spleen by CT [ Time Frame: 0-6 months ]
- Change in Peripheral Insulin Sensitivity [ Time Frame: 0-6 months ]Change in the rate of glucose disposal (Rd) during the low dose clamp. During a clamp procedure, insulin is infused at a dose based on body size and a glucose solution is infused and the rate adjusted every 5 minutes based on a blood glucose reading to maintain the blood glucose stable at 90 mg/dl (normal level). Using glucose isotopes and the rate of the glucose infusion, we are then able to calculate how much glucose the liver is producing and how much glucose is being taken up into tissues. This provides a measure of insulin sensitivity.
- Change in Intra-abdominal Fat Area by CT Scan [ Time Frame: 0-6 months ]
- Change in Hepatic Insulin Sensitivity [ Time Frame: 0-6 months ]Hepatic insulin sensitivity was determined using stable glucose isotope measurements during the low dose hyperinsulinemic euglycemic clamp to determine the rate of endogenous glucose production in the fasting state and in response to a low dose glucose infusion. The ability of insulin to suppress glucose, which is mainly produced by the liver, thus provides a measure of hepatic insulin sensitivity and is expressed as a percentage of the basal state. Change in the ability of low dose insulin to suppress endogenous glucose production during a labeled hyperinsulinemic euglycemic clamp.
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| Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
Control subjects: nl liver enzymes and no history of liver disease Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated alanine aminotransferase (ALT) and fatty liver by computerized tomography (CT) scan or ultrasound
- Able to comply with taking 1 pill a day for 6 months and follow-up safety visits
Exclusion Criteria:
- Cases: cirrhosis on liver biopsy or by clinical exam or fibrosis score
- Causes of liver dysfunction other than NASH
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Use of medications associated with hepatic steatosis:
- glucocorticoids
- estrogens
- tamoxifen
- amiodarone
- accutane
- sertraline
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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 hemoglobin A1c (HbA1c) >7.5% or use of insulin, metformin, rosiglitazone or pioglitazone
- Liver transaminases: ALT >5x upper limit of normal,
- 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 or since the liver biopsy
- History of significant coronary artery disease or congestive heart failure, retinopathy
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): NCT01289639
| United States, Washington | |
| VA Puget Sound Health Care System, Seattle | |
| Seattle, Washington, United States, 98108 | |
| Principal Investigator: | Kristina M Utzschneider, MD | VA Puget Sound Health Care System, Seattle |
| Responsible Party: | VA Office of Research and Development |
| ClinicalTrials.gov Identifier: | NCT01289639 |
| Other Study ID Numbers: |
CDA-2-044-08S-2 |
| First Posted: | February 4, 2011 Key Record Dates |
| Results First Posted: | October 20, 2014 |
| Last Update Posted: | August 17, 2017 |
| Last Verified: | July 2017 |
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non-alcoholic fatty liver disease non-alcoholic steatohepatitis insulin resistance pioglitazone fenofibrate |
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Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Insulin Resistance Digestive System Diseases Hyperinsulinism Glucose Metabolism Disorders Metabolic Diseases |
Pioglitazone Fenofibrate Hypoglycemic Agents Physiological Effects of Drugs Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents |