Clinical trial NCT01834300: 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
Overall status: COMPLETED
Phase: NA
Conditions: Non Alcoholic Fatty Liver Disease
Keywords: Hepatic insulin sensitivity
Muscle insulin sensitivity
B cell function
VLDL1 TG metabolism
VLDL2 TG metabolism
Lead sponsor: University of Liverpool
Sponsor class: OTHER
Collaborators: name: Royal Liverpool University Hospital
name: University of Surrey
name: Imperial College London
name: Royal Surrey County Hospital NHS Foundation Trust
First posted: 2013-04-17
Enrollment: 60
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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: 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.

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

Primary outcomes:
measure: Reduction in liver and muscle fat
timeFrame: 4 months
Secondary outcomes:
measure: Changes in liver function tests
timeFrame: 4 months
measure: Changes in lipid profiles
timeFrame: 4 months
measure: Changes in body weight and anthropometric measurements
timeFrame: 4 months
measure: Hepatic insulin sensitivity
timeFrame: 4 months
measure: VLDL-TG kinetics
timeFrame: 4 months
Other outcomes:
Locations:
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: Surrey
city: Guildford
country: United Kingdom
facility: University of Surrey
state: Surrey
city: Liverpool
country: United Kingdom
facility: John Moores University
city: Liverpool
country: United Kingdom
facility: University of Liverpool
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool University
city: London
country: United Kingdom
facility: Imperial College London
Study officials:
affiliation: University of Liverpool
name: Daniel Cuthbertson, BSc PhD MRCP
role: STUDY_DIRECTOR
affiliation: University of Surrey
name: Fariba Shojaee-Moradie, BSc PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.