Exercise and the Receptor for Advanced Glycation End Products (RAGE)

University of Michigan

Status: Completed

Conditions: Diabetes Mellitus, Type 2

Treatments: Behavioral: Aerobic Exercise

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03534687

HUM00146001

5R01DK109948-02 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This study examines the effects of 12-weeks of aerobic exercise training on the mechanisms driving RAGE-mediated inflammation in type 2 diabetic humans.

Full description

Activation of RAGE (receptor of advanced glycation endproducts (AGEs)), via binding of AGEs and other ligands, modulates the development and progression of diabetic complications through persistent and cyclic activation of nuclear factor-kappa beta. Targeting RAGE directly as a therapeutic strategy has largely been unsuccessful. However, RAGE signaling can be interrupted, in vivo, by ADAM10 (a disintegrin and metalloproteinase 10) directed proteolytic cleavage of the RAGE ectodomain, and thus creating a soluble isoform of RAGE (sRAGE) that is released from the cell and appears into the circulation. Maintaining high levels of circulating sRAGE is advantageous as sRAGE will sequester RAGE ligands and prevent RAGE cell signaling.

Although the exact mechanisms of ADAM10 mediated RAGE release remain undefined, calcium related and other signaling (SIRT1) impact ADAM10. Aerobic exercise presents a unique model for mechanistic study of RAGE release as muscle contraction induces robust calcium signaling, activates SIRT1, and provides stimuli for tissue remodeling and resolution of the metabolic profile that drives inflammation.

Enrollment: 50 patients

Sex: All

Ages: 40 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age 40-75 y
• Type 2 diabetes
• Overweight or obese (BMI 26-44 kg/m2)
• Fluency in English (written and verbal)

Exclusion criteria

• Age <40 or >75 y
• BMI <26 or >44 kg/m2
• Existing cardiovascular, cerebrovascular, renal, or hematological disease, or cancer
• Current use of tobacco
• Pregnant or lactating
• Medications that may interfere with study outcomes

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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50 participants in 2 patient groups

Aerobic Exercise Group

Experimental group

Description:

Aerobic Exercise (AE) subjects will come in for supervised, aerobic exercise training sessions 5 days a week for 12 weeks. Training will progress from 55% VO2max for week 1 (40 min session), to 60-65% VO2max for week 2 (50 min session), to \~70% VO2max for all other weeks (50 min session). Subjects will perform a warm-up and cool down (\~5 min each) that includes stretching exercises. Subjects will wear heart rate monitors during each training session to provide feedback of target heart rate. Intensity, duration, resting and exercise heart rates, and blood pressures will be recorded for each session. Follow-up VO2max tests will be performed at weeks 4 and 8 to monitor progress and adjust AE training intensity.

Treatment:

Behavioral: Aerobic Exercise

Control Group

No Intervention group

Description:

During the 12 week control period, subjects are to maintain their normal, daily-living activities. Control group participants will be given the option to enroll in the AE training group after completion of the original Control group trial period.