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

July 19, 2024 updated by: Jacob Haus, University of Michigan

Role of Exercise in the Prevention and Treatment of RAGE-Mediated Inflammation (RECEPTOR) Trial

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

50

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Aerobic Exercise Group
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.
Behavioral: Aerobic Exercise
12-week supervised aerobic exercise
No Intervention: Control Group
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quantify the Percentage Change in Basal Circulating sRAGE After 12-weeks of Supervised Aerobic Exercise Training.
Time Frame: Baseline and 12 weeks
Serum will be separated from blood samples collected in vacutainer tubes via centrifugation before and after 12-weeks of aerobic exercise training. sRAGE will be quantified in these serum samples via ELISA (Quantikine, Human RAGE Immunoassay) per manufacture's protocol.
Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quantify the Percentage Change in Basal Muscle RAGE Expression After 12-weeks of Supervised Aerobic Exercise Training.
Time Frame: Baseline and 12 weeks
Basal biopsy derived skeletal muscle RAGE expression will be determined from the vastus lateralis before and after 12-weeks of aerobic exercise training. RAGE expression will be quantified via Western Blot. Muscle samples (~10 mg) will be homogenized and protein concentration will be determined via BCA assay (Pierce). Samples (20 μg protein) will be diluted in SDS buffer, heated at 85 °C for 5 min, resolved via SDS-PAGE (Bio-Rad Laboratories, Hercules, CA) and transferred to a nitrocellulose or PVDF membrane. Blocking will occur for 1 h and primary antibody (RAGE; Abcam, Cambridge, MA) incubation will occur overnight at 4 °C and quantified vs a standard or total protein.
Baseline and 12 weeks
Quantify the Percentage Change in Aerobic Capacity (VO2max) After 12-weeks of Supervised Aerobic Exercise Training.
Time Frame: Baseline and 12 weeks
Maximal oxygen consumption (VO2max) will be established via indirect calorimetry during an incremental treadmill test (Modified Bruce protocol) before and after 12-weeks of aerobic exercise training. Criteria, such as, rating of perceived exertion >18, respiratory exchange ratio >1.10, no further increase in VO2 despite increasing workloads, heart rate greater than age-predicted maximum, or volitional fatigue will be used to indicate a successful VO2max was achieved.
Baseline and 12 weeks
Quantify the Percentage Change in Insulin Sensitivity After 12-weeks of Supervised Aerobic Exercise Training.
Time Frame: Baseline and 12 weeks
Insulin sensitivity will be established via calculation of Matsuda Index from glucose and insulin values obtained every 30 minutes during a 75 g Oral GlucoseTolerance Test. Data are represented as percent change. Any change greater than a value of zero indicates an improvement in insulin sensitivity.
Baseline and 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Michigan

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Principal Investigator: Jacob Haus, PhD, University of Michigan

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 20, 2018

Primary Completion (Actual)

May 8, 2023

Study Completion (Actual)

May 8, 2023

Study Registration Dates

First Submitted

May 11, 2018

First Submitted That Met QC Criteria

May 11, 2018

First Posted (Actual)

May 23, 2018

Study Record Updates

Last Update Posted (Actual)

August 13, 2024

Last Update Submitted That Met QC Criteria

July 19, 2024

Last Verified

July 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HUM00146001
  • 5R01DK109948-02 (U.S. NIH Grant/Contract)

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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