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

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.

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