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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Behavioral: Aerobic Exercise


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerobic Exercise Group<br>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<br>* 12-week supervised aerobic exercise<br>|
| No Intervention: Control Group<br>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?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantify the change in basal circulating sRAGE after 12-weeks of supervised aerobic exercise training. | 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 change in basal muscle RAGE expression after 12-weeks of supervised aerobic exercise training. | 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 change in aerobic capacity (VO2max) after 12-weeks of supervised aerobic exercise training. | 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 change in insulin sensitivity after 12-weeks of supervised aerobic exercise training. | 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. | Baseline and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, RAGE, ADAM10, sRAGE