Diabetes, Exercise and Liver Fat (DELIVER)
Condition: Type 2 Diabetes Mellitus; Non-Alcoholic Fatty Liver Disease; Obesity; Insulin Resistance; Liver Diseases; Fatty Liver; Diabetes Mellitus; Glucose Metabolism Disorders; Glucose Intolerance; Metabolic Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Metabolic Diseases; Glucose Metabolism Disorders; Glucose Intolerance
Study type: Interventional

Summary: 
      This randomised controlled trial will determine if exercise (150 - 200 min per week, 6 weeks)
      can beneficially modify liver fat quality in non alcohol fatty liver disease patients with
      type 2 diabetes mellitus (n = 26, 13 per group). Liver fat quality will be assessed via
      magnetic resonance (3T) spectroscopy (1H-MRS) using validated methods.
    

Detailed description: 
      Verbal eligibility check

      Prior to commencing the study, participants will be contacted via telephone and an initial
      verbal eligibility check will take place (approx. 30 min conversation). Following this,
      potentially eligible participants will be invited to visit the Sir Peter Mansfield Imaging
      Centre for study assessment visit one.

      Assessment visit 1 - Sir Peter Mansfield Imaging Centre (University of Nottingham) Informed
      consent Before any study related procedures can take place, the participant must sign and
      date the most recent approved version of the Informed Consent Form. Before consent is
      obtained the responsible individual will ensure that the participant fully understands all
      aspects of the study. It will also be clearly stated that the participant is free to withdraw
      from the study at any time, for any reason, without prejudice to future care, and with no
      obligation to give the reason for withdrawal. If a participant withdraws from the study but
      does not withdraw their consent, then data already obtained may be used for the study. If a
      participant has withdrawn due to an adverse event, a medical professional will follow up as
      appropriate.

      The consent form will be signed and dated based up on an informed decision. The consent
      process will be performed by someone who has received consent training, has been authorised
      by the Chief Investigator, and is named on the delegation of authority log. The original
      signed form will be retained at the study site and copy will be given to the participant. A
      third copy will be posted to the participant's GP.

      Questionnaires

      Participants will complete several pen and paper based questionnaires to assess their
      eligibility to participate in the study and to provide baseline study data. These will
      include the following:

        -  Physical Activity Readiness Questionnaire - to determine participants' readiness to
           exercise and/or contraindications

        -  Loughborough University Health Screen Questionnaire - to obtain an overview of
           participants' medical history, current medications and family history of disease

        -  Sir Peter Mansfield Imaging Centre Magnetic Resonance Safety Screening Form - to assess
           potential contraindications to MRI

        -  Demographics & contact details - to determine participants' date of birth, ethnicity and
           postal address

        -  Alcohol intake questionnaire - to determine participant's habitual alcohol intake in
           order to classify as non-alcoholic fatty liver disease.

      Anthropometry, blood pressure and finger prick blood test Height, body mass and waist
      circumference will be measured using standard techniques and body mass index (BMI) will be
      calculated. Body fat percentage will be estimated using bioelectrical impedance analysis.
      Blood pressure will be assessed using an automated monitor after participants have sat
      quietly for 10 minutes (average of three measurements). A finger prick blood test will be
      taken to check preliminary eligibility (HbA1c) using a point-of-care device.

      Magnetic resonance imaging (MRI) MRI data will be acquired using a 3T Philips Ingenia MRI
      scanner. Liver fat quality indices and total intrahepatocellular liver fat fractions will be
      determined using 1H-MRS via the quantification of individual lipid group peaks. Liver
      inflammation, visceral adipose tissue and subcutaneous abdominal adipose tissue will be
      measured via MRI. The techniques used to measure these outcomes have been validated and
      published previously.

      Familiarisation with weighed food records and physical activity monitors Participants will be
      provided with a wrist worn (watch-like) physical activity monitor (GENEactiv) that they will
      wear 24 h/day for the next seven days. Participants will also be shown how to keep an
      accurate weighed food record and will be provided with food scales and diary to facilitate a
      three day record within the next seven days (two week and one weekend day).

      After this session, MRI scans will be assessed to examine whether or not participants have an
      amount of liver fat that if high enough for inclusion in the study (> 5.56%). If liver fat is
      less than this then participants will not be permitted to participate. If liver fat is equal
      to or greater than this level then participants will be invited to attend study assessment
      visit two.

      Assessment visit 2 - Leicester General Hospital (Leicester Diabetes Centre)

      Fasting blood sample

      Participants will be asked to attend the second study assessment visit having not eaten since
      the prior evening. These visits will therefore occur in the morning (before 10:30). At the
      start of this visit participants will provide a fasting venepuncture blood sample (40 mL
      blood) after having sat down for 10 minutes. This sample will be collected from an
      antecubital vein by an individual trained and experienced in phlebotomy. One blood bottle
      will be sent to hospital pathology labs for the analysis of glycated haemoglobin. The
      remaining samples will be spun immediately in a refrigerated centrifuge to obtain
      plasma/serum. These samples will subsequently be stored until the end of the trial within -80
      degrees (celsius) freezers at the research sites. Following the last participants visit,
      samples will be transported to Loughborough University (at -80 degrees ) by a commercial
      courier. Samples will then be analysed in batch for:

        -  Lipids

        -  C-reactive protein

        -  Liver enzymes

        -  Glucose

        -  Insulin

        -  Nonesterifed fatty acids

        -  Hepatokines

        -  Inflammatory proteins

      Medical evaluation and aerobic fitness A medical professional will take a full medical
      history from participants in order to identify any factors that may prohibit individuals from
      completing the study. A 12 lead ECG will also be performed. Finally, a symptom limited
      progressive treadmill exercise test will be undertaken on a treadmill. This test will require
      participants to exercise at increasingly harder intensities until volitional exhaustion. A
      clinical professional will monitor participants' blood pressure and ECG during this test
      which will be terminated if clinically indicated.

      Randomisation After visit two participants will be randomised (1:1) to condition (exercise
      training or control). Randomisation will be performed by a trial statistician (see section 13
      for additional details). The involvement of participants who are only completing Part A of
      the study will end at this point.

      Six week intervention Participants randomised to control will receive no interventions during
      the six week intervention phase. During this time, control participants will be asked to not
      change any aspects of their lifestyles. Ahead of week five, participants will be posted a
      physical activity monitor to wear continuously during week five and six. Participants will
      also complete weighed food diaries during week five (two week days and one weekend day).

      Participants randomised to exercise training will complete four exercise training sessions
      per week during the six week intervention. Each week, one session will be supervised by the
      research team whilst three sessions of brisk walking will be undertaken unsupervised by the
      participant. All exercise sessions will be composed of continuous moderate-intensity exercise
      and last 35 - 50 minutes in duration (depending on intervention week).

      Assessment visit 3 (post-intervention) - Sir Peter Mansfield Imaging Centre (University of
      Nottingham) The assessments undertaken at visit three will be a repeat of those completed
      during visit one.

      Assessment visit 4 (post-intervention) - Leicester General Hospital (Leicester Diabetes
      Centre) The assessments undertaken at visit four will be a repeat of those completed during
      visit two except that a medical examination will not be performed.
    

Intervention name(s): Exercise
Intervention type(s): Behavioral
Intervention description(s): 24 moderate-intensity exercise training sessions over six weeks (four times per week; ~50 min per session)
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A randomised control trial. Participants are randomised to an exercise group (treatment) or a control group (usual care/no treatment) for 6 weeks. Assessments occur at baseline and after 6 weeks
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Type 2 diabetes; Non-alcohol fatty liver disease; Exercise; Saturated fat; MRI; Proton magnetic resonance spectroscopy