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

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ClinicalTrials.gov Identifier: NCT03534687
Recruitment Status : Recruiting
First Posted : May 23, 2018
Last Update Posted : April 8, 2021
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Jacob Haus, University of Michigan

Tracking Information
First Submitted Date  ICMJE May 11, 2018
First Posted Date  ICMJE May 23, 2018
Last Update Posted Date April 8, 2021
Actual Study Start Date  ICMJE December 20, 2018
Estimated Primary Completion Date June 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 11, 2018)
Quantify the 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2018)
  • Quantify the 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.
  • Quantify the 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.
  • Quantify the change in insulin sensitivity after 12-weeks of supervised aerobic exercise training. [ Time Frame: Baseline and 12 weeks ]
    Insulin sensitivity will be established via hyperinsulinemic-euglycemic clamp before and after 12-weeks of aerobic exercise training. After the initial basal period of this procedure, a primed-continuous infusion (40mU/m2/min) of human insulin (Humulin-R, Eli Lilly & Co.) will be initiated and maintained for a period of 120 min. Glucose levels will be clamped at 90 mg/dL by use of a variable glucose infusion (20% dextrose). Blood glucose will be measured every 5 min to monitor levels and used to adjust the variable glucose infusion rate. The clamp procedure will be completed after the 120-min period of hyperinsulinemia or until steady state glucose concentration is achieved.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Exercise and the Receptor for Advanced Glycation End Products (RAGE)
Official Title  ICMJE Role of Exercise in the Prevention and Treatment of RAGE-Mediated Inflammation (RECEPTOR) Trial
Brief Summary This study examines the effects of 12-weeks of aerobic exercise training on the mechanisms driving RAGE-mediated inflammation in type 2 diabetic humans.
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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Diabetes Mellitus, Type 2
Intervention  ICMJE Behavioral: Aerobic Exercise
12-week supervised aerobic exercise
Study Arms  ICMJE
  • 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.
    Intervention: Behavioral: 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.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 11, 2018)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date June 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jacob Haus, PhD 734-647-2790 jmhaus@umich.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03534687
Other Study ID Numbers  ICMJE HUM00146001
5R01DK109948-02 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Jacob Haus, University of Michigan
Study Sponsor  ICMJE University of Michigan
Collaborators  ICMJE National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators  ICMJE
Principal Investigator: Jacob Haus, PhD University of Michigan
PRS Account University of Michigan
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP