Exercise to Restore 24h Rhythms in Metabolism

Recent evidence shows that pre-diabetes is characterized by marked alterations in 24h substrate metabolism, indicating metabolic inflexibility with an inability to fully switch to fat oxidation during the night. Whereas exercise has been shown to promote mitochondrial function and insulin sensitivity, it is unknown to if exercise training is able to restore 24h rhythmicity in overall substrate metabolism and muscle metabolism in human subjects with pre-diabetes.

In this single-arm longitudinal design, subjects will serve as their own control. Subjects will perform high-intensity interval training for 12 weeks (3x times per week) on a cycle ergometer at the research facility. Pre and post exercise, subjects will stay in a metabolic chamber and adhere to a relatively normal life-style in order to standardize the main 24h measurement period. As the primary outcome, substrate metabolism will be measured with a ventilated hood system and by indirect calorimetry in the chambers. Muscle biopsies from the vastus lateralis and frequent blood samples will also be taken over the course of the 24h. Thereby, ex-vivo skeletal muscle mitochondrial function and muscle clock gene expression will serve as the main secondary outcomes.

Inclusion criteria

• Caucasian
• Healthy (as determined by dependent physician)
• Overweight: BMI 25 - 35 kg/m2
• Prediabetic based on one or a combination of the following criteria:

• Impaired Glucose Tolerance (IGT): plasma glucose values ≥ 7.8 mmol/l and ≤ 11.1 mmol/l 120 minutes after glucose drink consumption during OGTT in screening.
• Impaired Fasting Glucose (IFG): Fasting plasma glucose ≥ 6.1 mmol/l and ≤ 6.9 mmol/l.
• Insulin Resistance: glucose clearance rate ≤ 360ml/kg/min, as determined using the OGIS120 model.
• HbA1c of 5.7-6.4%.
• Regular sleeping time (normally 7 - 9h daily)
• Stable dietary habits: no weight gain or loss > 3kg in the last three months.

Exclusion criteria

• Use of anticoagulants
• Previously diagnosed with type 2 diabetes
• Current alcohol consumption > 20 grams alcohol/day
• Extreme early bird or extreme night person (score ≤ 30 or ≥ 70 on MEQ-SA questionnaire)
• Heavily varying sleep-wake rhythm
• Nightshift work during last 3 months
• Travel across > 1 time zone in the last 3 months
• Significant food allergies/intolerance (seriously hampering study meals)
• Using > 400mg caffeine daily (more than 4 coffee or energy drink)
• Smoking