Precision Exercise Therapeutics (PET-pilot)

Individual Responses in Insulin Sensitivity to Different Exercise Modalities in Persons With Overweight: a Randomized Cross-over Pilot Study

The aim of this randomized cross-over study is to collect information for the design of a precision exercise therapy cohort that will predict what modality of physical activity a physically inactive individual with overweight should perform to increase insulin sensitivity given their unique biology, environment, and context.

This pilot study is needed prior to launching precision therapeutics programs, with the purpose to decrease the risk of research waste, increase the reliability of the experimental tests and estimate adequate sample size. 25 participants will be recruited to undergo three sets of experiments. An experiment consists of one exercise bout followed by an assessment of whole-body insulin sensitivity (measured from a oral glucose tolerance test) 1 and 2 days following the completion of the exercise bout yielding 19 study days of 3 hours each across 7 weeks, including the baseline measurement. The exercise modalities include 1) continuous aerobic exercise, 2) high intensity exercise and 3) resistance exercise training. A set consists of test-retest of the same experiment. The objectives of this pilot study are to assess the longevity of the increased whole-body insulin sensitivity in the days following different exercise modalities To estimate the intra-individual differences of different exercise modalities on whole-body insulin sensitivity the days following the last exercise bout To assess the fidelity of the test- and exercise protocols

Participants will be randomly allocated, following successful completion of the baseline measurements. An independent statistician generates a computer-generated randomization schedule including six possible sequence orders using balanced blocks, stratified by sex. The schedule will be forwarded to a secretary not involved in any study procedures and will be stored on a password-protected computer. Sequentially numbered (according to the sequence) opaque, sealed envelopes will be prepared and stored in a locked cabinet in an access restricted room. The envelopes will be lined with aluminum foil to render the envelope impermeable to light. Following the baseline measurements, a study nurse, not involved with any study procedures, will open the envelope, and inform the researcher about the order. The participant be informed about the trial condition upon arrival to lab for the experiments (i.e. on the first morning of each set of trial conditions).

The participants will complete a 10-min warm up, followed by 40 min of continuous aerobic exercise at an individualized intensity at 64-76% of the maximal heart rate HRmax on a bicycle ergometer/walking.

The training consists of 10 minutes of warm up followed by 25 minutes of high intensity interval training (5 bouts of 4 min at >85% HRmax interspaced by 4 minutes of low intensity training) and finally a 4 min cool-down.

The participants will complete moderate intensity whole-body resistance training. This will consist of 4 sets with 4 exercises (leg press, chest press, back row, leg extension in appropriate machines) with a brief warm-up prior to each exercise. Each set will be interspersed by 2-min breaks. Each set (including breaks) will thus equate to 2.5 min. Intensity will be set a 12-repetition max (RM, i.e., can repeated no more than 12 times) or 10 repetitions with 1-2 repetitions in reserve (i.e., 10 repetitions where failure would occur within 1-2 more repetitions).

The "Continuous aerobic exercise" session will be performed in total two times, as it will be repeated in sets on consecutive weeks (e.g. Two Tuesdays in a row) with a 1-week wash-out period. The " Continuous aerobic exercise" intervention is matched to the other arms on the time spend for each bout equating a total of 50 minutes of exercise per session. An oral glucose tolerance test will be performed 24 hours and 48 hours after the exercise bout.

The "High intensity interval training" session will be performed in total two times, as it will be repeated in sets on consecutive weeks (e.g. Two Tuesdays in a row) with a 1-week wash-out period. The "High intensity interval training" intervention is matched to the other arms on the time spend for each bout equating a total of 50 minutes of exercise per session. An oral glucose tolerance test will be performed 24 hours and 48 hours after the exercise bout.

The "Resistance training" session will be performed in total two times, as it will be repeated in sets on consecutive weeks (e.g. Two Tuesdays in a row) with a 1-week wash-out period. The "Resistance training" intervention is matched to the other arms on the time spend for each bout equating a total of 50 minutes of exercise per session. An oral glucose tolerance test will be performed 24 hours and 48 hours after the exercise bout.

24 hour change in insulin sensitivity (Oral glucose insulin sensitivity index) derived from a 2-hour Oral Glucose Tolerance Test

Difference between exercise modalities in the change in whole-body insulin sensitivity (Oral glucose insulin sensitivity index) from baseline to 24 hours following the exercise bout

24 hour change in insulin sensitivity (Matsuda index) derived from a 2-hour Oral Glucose Tolerance Test

Difference between exercise modalities in the change in whole-body insulin sensitivity (Matsuda index) from baseline to 24 hours following the exercise bout

48 hour change in insulin sensitivity (Oral glucose insulin sensitivity index) derived from a 2-hour Oral Glucose Tolerance Test

Difference between exercise modalities in the change in whole-body insulin sensitivity (Oral glucose sensitivity index) from baseline to 48 hours following the exercise bout

48 hour change in insulin sensitivity (Matsuda index) derived from a 2-hour Oral Glucose Tolerance Test

Difference between exercise modalities in the change in whole-body insulin sensitivity (Matsuda index) from baseline to 48 hours following the exercise bout

24 to 48 hour change in insulin sensitivity (Oral glucose insulin sensitivity index) derived from a 2-hour Oral Glucose Tolerance Test

Difference between exercise modalities in the change in whole-body insulin sensitivity (Oral glucose sensitivity index) from 24 hours to 48 hours following the exercise bout

24 to 48 hour change in insulin sensitivity (Matsuda index) derived from a 2-hour Oral Glucose Tolerance Test

Difference between exercise modalities in the change in whole-body insulin sensitivity (Matsuda index) from 24 hours to 48 hours following the exercise bout

Variation in insulin sensitivity (Oral glucose sensitivity index) derived from a 2-hour Oral Glucose Tolerance Test

Mean and standard deviations of intra- and inter-individual differences in whole-body insulin sensitivity (Oral glucose sensitivity index) in response to different exercise modalities 1 and 2 days following the previous exercise bout.

Mean and standard deviations of intra- and inter-individual differences in whole-body insulin sensitivity (Matsuda index) in response to different exercise modalities 1 and 2 days following the previous exercise bout.

Mean and standard deviations of intra- and inter-individual differences in fasting and post-prandial (derived from an OGTT) plasma glucose in response to different exercise modalities 1 and 2 days following the previous exercise bout.

Mean and standard deviations of intra- and inter-individual differences in fasting and post-prandial (derived from an OGTT) plasma insulin in response to different exercise modalities 1 and 2 days following the previous exercise bout.

Mean and standard deviations of intra- and inter-individual differences in fasting and post-prandial (derived from an OGTT) plasma C-peptide in response to different exercise modalities 1 and 2 days following the previous exercise bout.

Mean and standard deviations of intra- and inter-individual differences in fasting and post-prandial (derived from an OGTT) urinary C-peptide in response to different exercise modalities 1 and 2 days following the previous exercise bout.

Mean and standard deviations of intra- and inter-individual differences in post-prandial (from an OGTT) gastric empyting, measured by paracetamol, in response to different exercise modalities 1 and 2 days following the previous exercise bout.

Mean and standard deviations of intra- and inter-individual differences in free living physical activity (measured by accelerometers) in response to different exercise modalities

Mean and standard deviations of intra- and inter-individual differences in continuous glucose (measured by continuous glucose monitors) in response to different exercise modalities

Mean and standard deviations of intra- and inter-individual differences in psychosocial stress (measured by questionnaires) in response to different exercise modalities

Feasibility will be assessed using a qualitative questionnaires. Subject domains include e.g. participant satisfaction with 1) time spend on test- and training, 2) the recruitment process, 3) communication regarding participation and 4) the written information about participation, 5) acceptability of the tests.

Inclusion Criteria: BMI>25 Age> 40 years Inactivity, defined as < 1,5 hours of structured physical activity pr. week at moderate intensity and cycling < 30 minutes/5 km pr. day at moderate intensity (moderate intensity = out of breath but able to speak) Exclusion Criteria: • HbA1c>53 mmol/mol Uncontrolled hypertension Uncontrolled hyperlipidemia, Known hyperthyroid disease Endocrine disorders causing obesity Known autoimmune disease Unstable cardiovascular disease Glucose lowering medications except for low dose metformin (=<1000 mg/day) Current treatment with anti-inflammatory medication, unless pain killers without prescription No participation in other research intervention studies Pregnancy/considering pregnancy within the study period Conditions countering exercise