Ischemia-reperfusion Exercise Study

Effect of Ischemia on the Insulin-sensitizing Effect of Exercise

The study investigates the relationship between activation of AMP-activated protein kinase (AMPK) in human skeletal muscle and the subsequent improvement in muscle insulin sensitivity for the stimulation of glucose uptake.

This will be investigated in young healthy lean male subjects.

Study Overview

• Status: Completed
• Conditions: Insulin Sensitivity
• Intervention / Treatment: Other: Exercise, insulin infusion

Detailed Description

This study aims to demonstrate the association between AMPK activation and increased insulin sensitivity in human skeletal muscle. The investigators intend to examine insulin sensitivity after various levels of AMPK activation in skeletal muscle that includes exercise at different intensities as well as exercise combined with leg blood flow restriction (ischemia). The hypothesis is that exercise combined with ischemia will result in an increased activation of AMPK compared to exercise alone, and therefore it is expected that exercise combined with ischemia will result in the greatest improvement in muscle insulin sensitivity.

Methods:

The main experiment consists of 3 experimental days (A, B and C), separated by a minimum of 14 days and carried out in a randomised order. On all the study days, the participants will arrive in the laboratory after an overnight fast. Catheters will be placed in both femoral veins and in one femoral artery. A muscle biopsy will be obtained from vastus lateralis of one leg (resting leg). Experiment A consists of one-legged muscle work for 1 hour at 70% of the leg maximum aerobic work capacity with the other leg serving as a resting control. In experiment B, the same work are performed, but with periodic at the same constricting the blood supply to the working leg (25 seconds every 2 min). Experiment C consists of one-legged muscle work for 1 hour at 70% and 95% of the leg maximum aerobic work capacity (alternately every 5 min). Immediately after each type of exercise a biopsy will be obtained from the exercising leg and the participants will rest in the fasted state for 3 hours before a third set of muscle biopsies (from both legs) will be obtained. Subsequently, insulin sensitivity will be evaluated in the participants during a 2-hour physiological hyperinsulinemic euglycemic clamp. By the end of the clamp, a final set of biopsies (both legs) will be obtained. Throughout the study day sampling of artery and venous blood/plasma samples allows for the estimation of substrate extraction by the two legs. Further, measures of artery blood flow by Ultrasound Doppler technique allow for the final calculation of substrate uptake/release across the two legs before exercise, during exercise and in recovery from exercise. Importantly, the ability for insulin to stimulate these processes can be evaluated in both a rested and in a prior exercised leg.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • København, Denmark, 2100
    • Department of Exercise, Nutrition and Sports, Faculty of Sciences, University of Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• normal weight (BMI: below or equal to 27)
• physical active on a regular basis
• cardiorespiratory fitness between 40-60 ml/kg/min
• no history or sign of type 2 diabetes, hypertension, insulin resistance or dyslipidemia

Exclusion Criteria:

• smoker
• BMI: above 27
• using any kind of medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low intensity exercise; 70% of maximal leg work load capacity	Other: Exercise, insulin infusion; Acute one-legged exercise, Insulin infusion 3 hours after one-legged exercise
Experimental: High intensity exercise; 70% and 95% of maximal work load capacity (alternately every 5 min)	Other: Exercise, insulin infusion; Acute one-legged exercise, Insulin infusion 3 hours after one-legged exercise
Experimental: Low intensity exercise + intermittent ischemia-reperfusion; 70% of maximal leg work load capacity with intermittent ischemia (25 seconds every 2 min)	Other: Exercise, insulin infusion; Acute one-legged exercise, Insulin infusion 3 hours after one-legged exercise

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle glucose uptake during exercise and enhanced insulin sensitivity in recovery from exercise.	Leg glucose uptake is calculated by the arterial-venous difference i blood glucose concentration multiplied with leg blood flow. Sampling of artery and venous blood samples for blood glucose measurements. Measures of artery blood flow by Ultrasound Doppler technique allows a final calculation of glucose uptake across the legs before exercise, during exercise, in recovery from exercise and with insulin stimulation.	Through study completion, an average of 1 year.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AMPK activity in muscle biopsies	The obtained muscle samples will be subjected to protein kinase activity measurements.	5 years
Posttranslational modification of proteins in muscle biopsies	The obtained muscle samples will be subjected to standard western blotting for the evaluation of posttranslational modifications of various proteins involved in glucose metabolism.	5 years

Collaborators and Investigators

• Sponsor: University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2018
• Primary Completion (Actual): January 3, 2020
• Study Completion (Actual): January 3, 2020

Study Registration Dates

• First Submitted: April 29, 2021
• First Submitted That Met QC Criteria: April 29, 2021
• First Posted (Actual): May 4, 2021

Study Record Updates

• Last Update Posted (Actual): January 21, 2022
• Last Update Submitted That Met QC Criteria: January 5, 2022
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Exercise; Ischemia; Insulin Sensitivity; Glucose Uptake
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Hyperinsulinism; Hypersensitivity; Ischemia; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: ischemia

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No