Insulin Resistance in Non-alcoholic Fatty Liver Disease

Insulin Resistance in Non-alcoholic Fatty Liver Disease (Protocol Drug Change From Project Career Development Award (CDA)-2-044-08S)

The study is designed to investigate the relationship between insulin resistance and non-alcoholic fatty liver disease (NAFLD) 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.

Study Overview

• Status: Terminated
• Conditions: Fatty Liver
• Intervention / Treatment: Drug: placebo; Drug: fenofibrate; Drug: pioglitazone

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, 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
• Enrollment (Actual): 11
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System, Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

• 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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; matching placebo 1 po qd	Drug: placebo; placebo 1 capsule po qd
Experimental: Fenofibrate; micronized fenofibrate 200 mg 1 po qd	Drug: fenofibrate; micronized fenofibrate 200 mg 1 po qd; Other Names: micronized fenofibrate
Experimental: Pioglitazone; pioglitazone 30 mg po qd	Drug: pioglitazone; pioglitazone 30 mg po qd; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Liver/Spleen Ratio Measured as the Ratio in Hounsfield Units Between the Liver and the Spleen on Computed Tomography (CT) Scan	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Alanine Aminotransferase (ALT) Levels		0-6 months
Change in Liver/Spleen Ratio Measure by the Density Ratio in Hounsfield Units Between the Liver and the Spleen by CT		0-6 months
Change in Peripheral Insulin Sensitivity	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.	0-6 months
Change in Intra-abdominal Fat Area by CT Scan		0-6 months
Change in Hepatic Insulin Sensitivity	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.	0-6 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Kristina M 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: October 1, 2005
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: January 21, 2011
• First Submitted That Met QC Criteria: February 3, 2011
• First Posted (Estimate): February 4, 2011

Study Record Updates

• Last Update Posted (Actual): August 17, 2017
• Last Update Submitted That Met QC Criteria: July 14, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: insulin resistance; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; pioglitazone; fenofibrate
• 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; Pioglitazone; Fenofibrate
• Other Study ID Numbers: CDA-2-044-08S-2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No