Insulin Resistance in Non-alcoholic Fatty Liver Disease

• ClinicalTrials.gov Identifier: NCT00252499
• Recruitment Status: Terminated
• First Posted: November 11, 2005
• Results First Posted: April 11, 2014
• Last Update Posted: August 20, 2014
• Sponsor: US Department of Veterans Affairs
• Information provided by (Responsible Party): VA Office of Research and Development ( US Department of Veterans Affairs )

Study Description

Brief Summary:

The purpose of this study is to determine whether nonalcoholic fatty liver disease (NAFLD) is associated with altered peripheral and hepatic insulin sensitivity and to investigate potential mechanisms underlying insulin resistance in NAFLD by determining associations between hepatic and peripheral insulin sensitivity, hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, beta-cell function and body fat distribution.

Condition or disease	Intervention/treatment	Phase
Fatty Liver; Insulin Resistance	Drug: rosiglitazone; Drug: fenofibrate; Drug: placebo for rosiglitazone; Drug: placebo for fenofibrate	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: Insulin Resistance in Non-alcoholic Fatty Liver Disease
• Study Start Date: October 2005
• Actual Primary Completion Date: August 2010
• Actual Study Completion Date: August 2010

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo Arm; matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd	Drug: placebo for rosiglitazone; placebo tablets that are matched to look like rosiglitazone; Drug: placebo for fenofibrate; placebo matched to look like fenofibrate tablets
Experimental: Rosiglitazone Arm; rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd	Drug: rosiglitazone; PPAR-gamma agonist, insulin sensitizer; Drug: placebo for fenofibrate; placebo matched to look like fenofibrate tablets
Experimental: Fenofibrate Arm; micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid	Drug: fenofibrate; PPAR-alpha agonist, reduces triglycerides; Drug: placebo for rosiglitazone; placebo tablets that are matched to look like rosiglitazone

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months [ Time Frame: 6 months ]
2. 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 ]
3. 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.
4. 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.
5. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Washington

VA Puget Sound Health Care System, Seattle

Seattle, Washington, United States, 98108

Sponsors and Collaborators

US Department of Veterans Affairs

Investigators

• Principal Investigator: Kristina Marie Utzschneider, MD; VA Puget Sound Health Care System, Seattle

More Information

Additional Information:

Click here for more information about this study: Insulin resistance in non-alcoholic fatty liver disease 

Publications of Results:

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.

• Responsible Party: US Department of Veterans Affairs
• ClinicalTrials.gov Identifier: NCT00252499
• Other Study ID Numbers: CDA-2-044-08S
• First Posted: November 11, 2005
• Results First Posted: April 11, 2014
• Last Update Posted: August 20, 2014
• Last Verified: August 2014

Keywords provided by VA Office of Research and Development ( US Department of Veterans Affairs ):

beta cell function; fenofibrate; non-alcoholic steatohepatitis; rosiglitazone; insulin sensitivity

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Insulin Resistance; Digestive System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Rosiglitazone; Fenofibrate; Hypoglycemic Agents; Physiological Effects of Drugs; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents