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Completed

NCT Number: NCT03534687

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

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

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Key information

Conditions

Diabetes Mellitus, Type 2 Alzheimer Disease 10 Behavior Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Motor Activity Nutritional and Metabolic Diseases

Age range

40 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University of Michigan

Ann Arbor, Michigan, 48109, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Aerobic Exercise

Behavioral

12-week supervised aerobic exercise

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. 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.

  3. 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.

Sponsors and collaborators

Lead sponsor

University of Michigan

Other

Collaborators

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

Registry information

Official study title

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

Important dates

Study start
2018
Primary completion
2023
Study completion
2023
First posted
May 23, 2018
Registry last updated
Aug 13, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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