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

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).

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.

Study Overview

• Status: Completed
• Conditions: Non Alcoholic Fatty Liver Disease
• Intervention / Treatment: Behavioral: Unsupervised exercise training; Behavioral: Supervised exercise training

Detailed Description

1. 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.

2. 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.

3. 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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • Liverpool, United Kingdom, L3 2ET
    • John Moores University
  • Liverpool, United Kingdom, L69 3GE
    • University of Liverpool
  • Liverpool, United Kingdom, L9 7AL
    • Liverpool University
  • London, United Kingdom, W12 0HS
    • Imperial College London
  • Surrey
    • Guildford, Surrey, United Kingdom, GU16 7UJ
      • Royal Surrey County Hospital
    • Guildford, Surrey, United Kingdom, GU27WG
      • University of Surrey

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Control; 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.	Behavioral: Unsupervised exercise training; 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.
Experimental: lifestyle counseling and exercise; 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.	Behavioral: Supervised exercise training; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in liver function tests	Biochemial measurements of the liver enzymes will be measured pre and post intervention period	4 months
Changes in lipid profiles	Total cholesterol, triglyceride and high density lipoprotien concentrations in fasting state will be measured pre and post intervention period.	4 months
Changes in body weight and anthropometric measurements	Body weight and waist to hip ratio will be measured pre and post intervention period.	4 months
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	4 months
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.	4 months

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: Imperial College London; Royal Liverpool University Hospital; University of Surrey; Royal Surrey County Hospital NHS Foundation Trust
• Investigators: Study Director: Daniel Cuthbertson, BSc PhD MRCP, University of Liverpool; Principal Investigator: Fariba Shojaee-Moradie, BSc PhD, University of Surrey

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2009
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: April 12, 2013
• First Submitted That Met QC Criteria: April 12, 2013
• First Posted (Estimated): April 17, 2013

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Hepatic insulin sensitivity; Muscle insulin sensitivity; B cell function; VLDL1 TG metabolism; VLDL2 TG metabolism
• Additional Relevant MeSH Terms: Metabolic Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Insulin Resistance
• Other Study ID Numbers: 09/H1008/1