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The Effect of Exercise Intervention on Insulin Resistance in Non-alcoholic Fatty Liver Disease (NAFLD)

Primary Purpose

Non Alcoholic Fatty Liver Disease

Status
Unknown status
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Unsupervised exercise training
Supervised exercise training
Sponsored by
University of Liverpool
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non Alcoholic Fatty Liver Disease focused on measuring Hepatic insulin sensitivity, Muscle insulin sensitivity, B cell function, VLDL1 TG metabolism, VLDL2 TG metabolism

Eligibility Criteria

20 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Sedentary, non smoking, male subjects,
  • Alcohol consumption men <21 units/week,
  • BMI 27-35. (Lean individuals do not suffer from NAFLD, so are not suitable for this study. Conversely, we are restricted to a maximum BMI of 35 due to the size limitations of the MR scanner.)
  • A clinical diagnosis of NAFLD based upon the following criteria: i) exclusion of other causes of liver disease i.e. negative Hepatitis B and C serology, a negative auto-immune profile and normal caeruloplasmin concentrations, ii) Ultrasound appearances suggestive of a fatty, echo-bright liver with no evidence of cirrhosis (in some cases, the diagnosis will have been confirmed histologically after liver biopsy.
  • Being willing to engage and motivated to follow an exercise program.

Exclusion Criteria:

  • Prescription of corticosteroids, amiodarone, tamoxifen, methotrexate (drugs known to cause secondary steatohepatitis) or fibrates. Statin is Ok as long as the patients are on stable therapy for a while, if changed then the patient will be excluded.
  • Alcohol consumption for men 21 units/week.
  • A contraindication to exercise (such as unstable ischaemic heart disease),
  • Type 2 diabetes (type 2 diabetes patients are excluded so that we are examining the involvement of insulin resistance at a reversible stage before β-cell failure has occurred).
  • Patients who are on medications that will interact with GTN (glyceryl trinitrate) will be excluded from the GTN dilatation (endothelial independent NO mediated function) aspect of the study.
  • Individuals who suffer from claustrophobia and have metal implants will be excluded from the MRI aspect of the study.
  • Patients who smoke will also be excluded from the study.
  • Total cholesterol >7

Sites / Locations

  • Royal Surrey County Hospital
  • University of Surrey
  • John Moores University
  • University of Liverpool
  • Royal Liverpool University Hospital
  • Liverpool University
  • Imperial College London

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Control

lifestyle counseling and exercise

Arm Description

Unsupervised exercise training This group will be given 1 hour lifestyle counseling by the exercise trainer after which they will have no contact with the exercise trainer to the end of the intervention period. The exercise intervention will be offered to the subjects once the post studies are completed.

Supervised exercise training Four months exercise training intervention will be either gym-based or patients will choose the mode of exercise that suits their lifestyle. Patients will be encouraged to exercise four times per week for 30-45 min at 60-80 % of maximal heart rate, with a 5 min warm-up and warm-down. Participants will be given free access to a variety of affiliated sports centres and will use the Wellness Key system, a software program that enables researchers to remotely track the exercise activity of participants very accurately. To ensure compliance with rest or exercise, all participants of both groups will have their mean physical activity level in 2 non-consecutive weeks evaluated with an ambulatory accelerometer.

Outcomes

Primary Outcome Measures

Reduction in liver and muscle fat
Tissue triglyceride content, or steatosis, will be accurately and non-invasively quantified in vivo using localized proton magnetic resonance spectroscopy (1H MRS).

Secondary Outcome Measures

Changes in liver function tests
Biochemial measurements of the liver enzymes will be measured pre and post intervention period
Changes in lipid profiles
Total cholesterol, triglyceride and high density lipoprotien concentrations in fasting state will be measured pre and post intervention period.
Changes in body weight and anthropometric measurements
Body weight and waist to hip ratio will be measured pre and post intervention period.
Hepatic insulin sensitivity
Half of the study cohort i.e. 30 individuals,15 exercise and 15 controls, will have peripheral and hepatic insulin sensitivity determined using a two-stage hyperinsulinaemic, euglycaemic clamp and use of deuterated glucose (2H2-glucose
VLDL-TG kinetics
The other half of the study cohort i.e. 30 individuals, 15 exercise and 15 controls, will have VLDL1 and VLDL2 TG kinetics determined using 5H2 glycerol bolus.

Full Information

First Posted
April 12, 2013
Last Updated
September 16, 2014
Sponsor
University of Liverpool
Collaborators
Royal Liverpool University Hospital, University of Surrey, Imperial College London, Royal Surrey County Hospital NHS Foundation Trust
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1. Study Identification

Unique Protocol Identification Number
NCT01834300
Brief Title
The Effect of Exercise Intervention on Insulin Resistance in Non-alcoholic Fatty Liver Disease (NAFLD)
Official Title
The Effects of Exercise Training on Visceral Fat, Insulin Sensitivity, β-cell Function and Triglyceride Kinetics in Patients With Non-alcoholic Fatty Liver Disease (NAFLD).
Study Type
Interventional

2. Study Status

Record Verification Date
September 2014
Overall Recruitment Status
Unknown status
Study Start Date
February 2009 (undefined)
Primary Completion Date
April 2013 (Actual)
Study Completion Date
June 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Liverpool
Collaborators
Royal Liverpool University Hospital, University of Surrey, Imperial College London, Royal Surrey County Hospital NHS Foundation Trust

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This project examines the effects of a 4 month structured exercise intervention program in patients with non-alcoholic fatty liver disease (NAFLD). We will examine changes in total and depot-specific (i.e.in different tissues, liver, muscle and pancreas)fat. We will correlate these with measurements of the insulin from the liver. The hypothesis is that by reducing fat in these specific depots we can reduce insulin resistance and prevent progression to diabetes.
Detailed Description
Exercise program: We are asking people to take part in a supervised exercise program for 4 months. This involves on average a weekly supervised exercise bout plus other unsupervised exercise bouts at home. We will ensure participants are physically able to embark on this by taking their medical history, physical examination and validated questionnaire (PARQ). This program is for the benefit on the patients' long term health. MR imaging to assess fat: occassionally these may pick up anomalies which require further investigation. A radiologist will screen the abdominal images and GP will be informed on anything requiring further investigation. No radiation is received during MR imaging. Physiological studies: Patients will be asked to attend for 2 non-consecutive days before and after the exercise intervention. Regular blood samples will be required as apart of these investigations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non Alcoholic Fatty Liver Disease
Keywords
Hepatic insulin sensitivity, Muscle insulin sensitivity, B cell function, VLDL1 TG metabolism, VLDL2 TG metabolism

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Control
Arm Type
Experimental
Arm Description
Unsupervised exercise training This group will be given 1 hour lifestyle counseling by the exercise trainer after which they will have no contact with the exercise trainer to the end of the intervention period. The exercise intervention will be offered to the subjects once the post studies are completed.
Arm Title
lifestyle counseling and exercise
Arm Type
Experimental
Arm Description
Supervised exercise training Four months exercise training intervention will be either gym-based or patients will choose the mode of exercise that suits their lifestyle. Patients will be encouraged to exercise four times per week for 30-45 min at 60-80 % of maximal heart rate, with a 5 min warm-up and warm-down. Participants will be given free access to a variety of affiliated sports centres and will use the Wellness Key system, a software program that enables researchers to remotely track the exercise activity of participants very accurately. To ensure compliance with rest or exercise, all participants of both groups will have their mean physical activity level in 2 non-consecutive weeks evaluated with an ambulatory accelerometer.
Intervention Type
Behavioral
Intervention Name(s)
Unsupervised exercise training
Intervention Description
The patients will be given lecture on lifestyle changes and its benefitial effects on health at the begining of the study by the exercise trainer. There will be no conatct with the exercise trainer for the period of intervention for 4 months.
Intervention Type
Behavioral
Intervention Name(s)
Supervised exercise training
Intervention Description
Patients will be encouraged to exercise four times per week for 30-45 min at 60-80 % of maximal heart rate, with a 5 min warm-up and warm-down. Participants will be given free access to a variety of affiliated sports centres and will use the Wellness Key system, a software program that enables researchers to remotely track the exercise activity of participants very accurately. To ensure compliance with rest or exercise, all participants of both groups will have their mean physical activity level in 2 non-consecutive weeks evaluated with an ambulatory accelerometer.
Primary Outcome Measure Information:
Title
Reduction in liver and muscle fat
Description
Tissue triglyceride content, or steatosis, will be accurately and non-invasively quantified in vivo using localized proton magnetic resonance spectroscopy (1H MRS).
Time Frame
4 months
Secondary Outcome Measure Information:
Title
Changes in liver function tests
Description
Biochemial measurements of the liver enzymes will be measured pre and post intervention period
Time Frame
4 months
Title
Changes in lipid profiles
Description
Total cholesterol, triglyceride and high density lipoprotien concentrations in fasting state will be measured pre and post intervention period.
Time Frame
4 months
Title
Changes in body weight and anthropometric measurements
Description
Body weight and waist to hip ratio will be measured pre and post intervention period.
Time Frame
4 months
Title
Hepatic insulin sensitivity
Description
Half of the study cohort i.e. 30 individuals,15 exercise and 15 controls, will have peripheral and hepatic insulin sensitivity determined using a two-stage hyperinsulinaemic, euglycaemic clamp and use of deuterated glucose (2H2-glucose
Time Frame
4 months
Title
VLDL-TG kinetics
Description
The other half of the study cohort i.e. 30 individuals, 15 exercise and 15 controls, will have VLDL1 and VLDL2 TG kinetics determined using 5H2 glycerol bolus.
Time Frame
4 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Sedentary, non smoking, male subjects, Alcohol consumption men <21 units/week, BMI 27-35. (Lean individuals do not suffer from NAFLD, so are not suitable for this study. Conversely, we are restricted to a maximum BMI of 35 due to the size limitations of the MR scanner.) A clinical diagnosis of NAFLD based upon the following criteria: i) exclusion of other causes of liver disease i.e. negative Hepatitis B and C serology, a negative auto-immune profile and normal caeruloplasmin concentrations, ii) Ultrasound appearances suggestive of a fatty, echo-bright liver with no evidence of cirrhosis (in some cases, the diagnosis will have been confirmed histologically after liver biopsy. Being willing to engage and motivated to follow an exercise program. Exclusion Criteria: Prescription of corticosteroids, amiodarone, tamoxifen, methotrexate (drugs known to cause secondary steatohepatitis) or fibrates. Statin is Ok as long as the patients are on stable therapy for a while, if changed then the patient will be excluded. Alcohol consumption for men 21 units/week. A contraindication to exercise (such as unstable ischaemic heart disease), Type 2 diabetes (type 2 diabetes patients are excluded so that we are examining the involvement of insulin resistance at a reversible stage before β-cell failure has occurred). Patients who are on medications that will interact with GTN (glyceryl trinitrate) will be excluded from the GTN dilatation (endothelial independent NO mediated function) aspect of the study. Individuals who suffer from claustrophobia and have metal implants will be excluded from the MRI aspect of the study. Patients who smoke will also be excluded from the study. Total cholesterol >7
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Cuthbertson, BSc PhD MRCP
Organizational Affiliation
University of Liverpool
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Fariba Shojaee-Moradie, BSc PhD
Organizational Affiliation
University of Surrey
Official's Role
Principal Investigator
Facility Information:
Facility Name
Royal Surrey County Hospital
City
Guildford
State/Province
Surrey
ZIP/Postal Code
GU16 7UJ
Country
United Kingdom
Facility Name
University of Surrey
City
Guildford
State/Province
Surrey
ZIP/Postal Code
GU27WG
Country
United Kingdom
Facility Name
John Moores University
City
Liverpool
ZIP/Postal Code
L3 2ET
Country
United Kingdom
Facility Name
University of Liverpool
City
Liverpool
ZIP/Postal Code
L69 3GE
Country
United Kingdom
Facility Name
Royal Liverpool University Hospital
City
Liverpool
ZIP/Postal Code
L7 8XP
Country
United Kingdom
Facility Name
Liverpool University
City
Liverpool
ZIP/Postal Code
L9 7AL
Country
United Kingdom
Facility Name
Imperial College London
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
27583475
Citation
Shojaee-Moradie F, Cuthbertson DJ, Barrett M, Jackson NC, Herring R, Thomas EL, Bell J, Kemp GJ, Wright J, Umpleby AM. Exercise Training Reduces Liver Fat and Increases Rates of VLDL Clearance But Not VLDL Production in NAFLD. J Clin Endocrinol Metab. 2016 Nov;101(11):4219-4228. doi: 10.1210/jc.2016-2353. Epub 2016 Sep 1.
Results Reference
derived
PubMed Identifier
27439593
Citation
Pugh CJ, Sprung VS, Jones H, Richardson P, Shojaee-Moradie F, Umpleby AM, Green DJ, Cable NT, Trenell MI, Kemp GJ, Cuthbertson DJ. Exercise-induced improvements in liver fat and endothelial function are not sustained 12 months following cessation of exercise supervision in nonalcoholic fatty liver disease. Int J Obes (Lond). 2016 Dec;40(12):1927-1930. doi: 10.1038/ijo.2016.123. Epub 2016 Jul 21.
Results Reference
derived

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The Effect of Exercise Intervention on Insulin Resistance in Non-alcoholic Fatty Liver Disease (NAFLD)

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