Fatty Liver, Insulin Resistance
Conditions
Keywords
beta cell function, fenofibrate, non-alcoholic steatohepatitis, rosiglitazone, insulin sensitivity
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.
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.
Interventions
DRUGrosiglitazone
PPAR-gamma agonist, insulin sensitizer
DRUGfenofibrate
PPAR-alpha agonist, reduces triglycerides
DRUGplacebo for rosiglitazone
placebo tablets that are matched to look like rosiglitazone
placebo matched to look like fenofibrate tablets
Sponsors
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Liver/Spleen Ratio at 6 Months | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Hepatic Insulin Sensitivity From Baseline to 6 Months | 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. |
| Change in Alanine Aminotransferase (ALT) Levels From Baseline to 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 | 6 months | — |
| Change in Peripheral Insulin Sensitivity From Baseline to 6 Months | 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. |
| Changes in Intra-abdominal Fat Area From Baseline to 6 Months | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited between 2006 and 2011 through referral from local gastroenterologists.
Pre-assignment details
Subjects underwent a screening visit prior to randomization to ensure that they qualified for the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd | 5 |
| Arm 2 rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd | 2 |
| Arm 3 micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid | 6 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Arm 2 | Arm 3 | Arm 1 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 6 Participants | 5 Participants | 13 Participants |
| Age, Continuous | 56.5 years STANDARD_DEVIATION 4.95 | 54.17 years STANDARD_DEVIATION 5.08 | 49.2 years STANDARD_DEVIATION 7.3 | 52.6 years STANDARD_DEVIATION 6.27 |
| Region of Enrollment United States | 2 participants | 6 participants | 5 participants | 13 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 5 | 0 / 2 | 4 / 6 |
| serious Total, serious adverse events | 0 / 5 | 0 / 2 | 0 / 6 |
Outcome results
Primary
Liver/Spleen Ratio at 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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Liver/Spleen Ratio at 6 Months | 0.85 ratio | Standard Error 0.08 |
| Arm 2 | Liver/Spleen Ratio at 6 Months | 0.96 ratio | Standard Error 0.25 |
| Arm 3 | Liver/Spleen Ratio at 6 Months | 0.60 ratio | Standard Error 0.17 |
Secondary
Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months | -11.5 U/L | Standard Error 12.9 |
| Arm 2 | Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months | -35.0 U/L | Standard Error 37 |
| Arm 3 | Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months | -15.2 U/L | Standard Error 4.5 |
Secondary
Change in Hepatic Insulin Sensitivity From Baseline to 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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Change in Hepatic Insulin Sensitivity From Baseline to 6 Months | 23.3 percent of baseline EGP | Standard Error 7.8 |
| Arm 2 | Change in Hepatic Insulin Sensitivity From Baseline to 6 Months | -4.09 percent of baseline EGP | Standard Error 4.34 |
| Arm 3 | Change in Hepatic Insulin Sensitivity From Baseline to 6 Months | 4.91 percent of baseline EGP | Standard Error 9.32 |
Secondary
Change in Peripheral Insulin Sensitivity From Baseline to 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.
Time frame: 6 months
Population: One person in Arm 1 dropped out and thus is lacking 6 month data. The 6 month isotope data to calculate the rate of glucose disposal was not available for one subject in Arm 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Change in Peripheral Insulin Sensitivity From Baseline to 6 Months | 1.65 mg/min/kg | Standard Error 2.11 |
| Arm 2 | Change in Peripheral Insulin Sensitivity From Baseline to 6 Months | 0.123 mg/min/kg | Standard Error 2.62 |
| Arm 3 | Change in Peripheral Insulin Sensitivity From Baseline to 6 Months | -0.24 mg/min/kg | Standard Error 1.14 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Change in the Liver Spleen Ratio by CT Scan From Baseline to 6 Months as a Measure of Fat in the Liver | .09 ratio | Standard Error 0.1 |
| Arm 2 | Change in the Liver Spleen Ratio by CT Scan From Baseline to 6 Months as a Measure of Fat in the Liver | .34 ratio | Standard Error 0.09 |
| Arm 3 | Change in the Liver Spleen Ratio by CT Scan From Baseline to 6 Months as a Measure of Fat in the Liver | -.16 ratio | Standard Error 0.1 |
Secondary
Changes in Intra-abdominal Fat Area From Baseline to 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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Changes in Intra-abdominal Fat Area From Baseline to 6 Months | 885 mm2 | Standard Error 874 |
| Arm 2 | Changes in Intra-abdominal Fat Area From Baseline to 6 Months | 440 mm2 | Standard Error 2788 |
| Arm 3 | Changes in Intra-abdominal Fat Area From Baseline to 6 Months | 108 mm2 | Standard Error 3416 |