Can Brisk Walking Combined With Ingestion of a Lipid-lowering Drug Improve Fat Metabolism in Muscle?

Diabetes UK, Liverpool University Hospitals NHS Foundation Trust, Royal Liverpool University Hospital

Briefly, participants will be assessed for their eligibility for the study using an oral glucose tolerance test, which involves drinking a sugary drink followed by a series of small blood samples. If eligible, participants will be asked to take part in a fitness test and then two trials which will involve walking on a treadmill at a steady pace. Before and after the exercise a small piece of muscle will be taken from their thigh under local anaesthesia, as well as several small blood samples. Muscle muscle samples will be assessed for lipid metabolites.

The accumulation of fat in skeletal muscle is linked with insulin resistance in obesity and T2D. However, fat also accumulates in the muscle of lean, healthy people, but they remain insulin sensitive. This is because healthy people are able to burn this fat to generate energy during exercise. However, overweight/obese inactive people can't use muscle fat during exercise in the same manner, which is related to the high blood lipid concentrations that are observed in these individuals. Acipimox is a lipid-lowering agent that specifically reduces the breakdown of fat in adipose tissue and has been shown improve the blood lipid profile of obese individuals and T2D patients, at least in the short-term (1-2 weeks). Previous research has shown that the combination of Acipimox with exercise restores the ability of obese people to burn fat during moderate-intensity cycling exercise. It is now important to test whether Acipimox also increases the ability to burn muscle fat during low-intensity walking in people with prediabetes. If it does, then the next step will be to test whether the combination of Acipimox and walking can lead to improved insulin sensitivity and reduced T2D risk over a longer intervention programme. Twelve people with pre-diabetes will be recruited to undertake two experimental trials in a randomised order. Each trial will involve walking for 45 minutes on a treadmill, with muscle biopsies obtained from the thigh before (basal), immediately following (post-exercise) and 3 h post-exercise. Each trial will be identical, except that participants will ingest either Acipimox or a placebo in a double-blind design. Muscle biopsies will be used to examine differences in muscle fat between the two trials.

This study involves 2 trials. Each trial will involve walking for 45 minutes on a treadmill, with muscle biopsies obtained from the thigh before (basal), immediately following (post-exercise) and 3 h post-exercise. Each trial will be identical, except that participants will ingest either Acipimox or a placebo in a double-blind design. Muscle biopsies will be used to examine differences in muscle fat between the two trials

Participants will undergo pre assessment testing of a body composition (DEXA), a maximal aerobic fitness test, and an oral glucose tolerance test. Following this, participants will ingest 250 mg of Acipimox, before undertaking 45 minutes walking on a treadmill. A muscle biopsy will be taken pre, immediately post and 3 hours post the walking trial. Blood samples will be taken at regular intervals throughout.

Participants will undergo pre assessment testing of a body composition (DEXA), a maximal aerobic fitness test, and an oral glucose tolerance test.Participants will then undergo a 45 minute walk on a treadmill with no Acipimox ingestion. A muscle biopsy will be taken pre, immediately post and 3 hours post the walking trial. Blood samples will be taken at regular intervals throughout.

Participants will complete a walking fitness text until exhaustion to determine maximal aerobic capacity.

Participants will give a small muscle sample pre-, immediately post and 3 hours post- the exercise trial to be assessed for lipid metabolites.

A change in the amount of fatty acids in the blood from baseline, to every 15 minute interval from the ingestion of acipimox up until 2 hours 45 minutes. From this point, samples will be every 30 minutes until 3 hours 45 minutes terminates the trial.

Muscle biopsies will be assessed for lipid metabolites using liquid chromatography-mass spectrometry.

Blood samples will be assessed for the amount of glycerol in the blood throughout the exercise trial.

A change in the amount of fatty acids in the blood from baseline, to every 15 minute interval from the ingestion of acipimox up until 2 hours 45 minutes. From this point, samples will be every 30 minutes until 3 hours 45 minutes terminates the trial.

Muscle samples will be analysed using confocal immunofluorescence microscopy for the amount of IMTG within the samples.

A change in amount of IMTG within the muscle from baseline, to immediately post and 3 hours post the exercise intervention.

Inclusion Criteria: Aged 25-55 years Overweight or obese (BMI >28 kg.m-2) Have prediabetes 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 intending to get pregnant during the study) 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 programmes or using weight loss medication Diagnosed with chronic kidney disease