Can the Health Benefits of a Walking-based Exercise Programme be Enhanced by Co-ingestion of a Lipid-lowering Drug?

Study investigates the hypothesis that an exercise programme of steady walking will have larger effects on insulin sensitivity and glycemic control when combined with Acipimox intake prior to each exercise session in people with pre-diabetes. Thirty-four sedentary, overweight/obese people (aged 25-50 years, BMI \>28 kg.m-2) with pre-diabetes will be recruited using the same strategy as study 2 and split into two groups (detailed below). Participants will undergo several pre- intervention assessments, followed by a 12-week walking based intervention combined with either Acipimox ingestion or no drug ingestion, pre- each exercise session. Following this, the post-assessment measures will identical to the pre-assessment measures.

Study 3 investigates the hypothesis that an exercise programme of steady walking will have larger effects on insulin sensitivity and glycaemic control when combined with Acipimox intake prior to each exercise session in people with prediabetes. Thirty-four sedentary, overweight/obese people (aged 25-50 years, BMI \>28 kg.m-2) with prediabetes will be recruited using the same strategy as study 2 and split into two groups (detailed below).

Pre-intervention assessments:

Visit 1: Participants will undergo an assessment of body composition (DXA) and undertake a graded treadmill walking test to estimate maximal aerobic fitness (VO2max).

Visit 2: Participants will be able to opt to undergo an MRI scan, taking place before breakfast. The MRI scan is used to measure fat stored in the liver and muscles. A continuous glucose monitoring (CGM) sensor will be inserted to measure insulin sensitivity.

Visit 3: Participants will arrive at the laboratory after an overnight fast (\>10 h) to undergo a Hyperinsulinaemic euglycaemic clamp to assess whole-body insulin sensitivity. Plasma glucose will be measured at regular intervals and muscle biopsies will be obtained from the vastus lateralis muscle of one leg before and after 2 hours of the clamp.

Exercise intervention: Pairs of participants from each group (matched for gender, age and VO2max) will be randomized to undertake 12 weeks of steady walking combined with ingestion of either Acipimox or placebo in a counter-balanced, double-blind design. Supervised treadmill walking sessions will be undertaken at LJMU three times per week, with exercise performed at a speed equivalent to 45% VO2max. Participants will initially exercise for 30 mins per session (weeks 1 and 2), and each session will increase in duration by 5 mins every 2 weeks thereafter, up to 50 minutes of exercise. 1 hour before each walking session, participants will ingest either 250 mg Acipimox or nothing.

Post-intervention assessments: The post-intervention assessments will be identical in all respects to the pre-intervention assessments and will be commenced ≥72 hours after the final training session.

Eligibility Criteria:
Inclusion Criteria:

* BMI \>28 kg.m-2
* Pre-diabetic
* Not currently using any anti-diabetes medication
* Physically inactive (performing less than two 30 min structured exercise sessions per week for the last year)
* Not pregnant or currently breast feeding
* Pre-menopausal
* Not currently involved in a weight loss programme or using weight loss medication

Exclusion Criteria:

* Involved in regular exercise (engaged in more than 2 sessions of structured exercise of \>30 min per week)
* Currently using anti-diabetes medication (e.g. insulin, metformin)
* Currently using niacin/vitamin B3 supplements
* Pregnant or breast feeding
* Currently engaged in active weight loss programme or using weight loss medication
* Diagnosed with chronic kidney disease