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-?B. 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. Our long-term goal is to identify strategies for the prevention and treatment of diabetic complications. Using aerobic exercise, we have elucidated a mechanism for ADAM10 upregulation to increase RAGE shedding. Aerobic exercise presents a unique model for mechanistic study of RAGE shedding as muscle contraction provides stimuli for tissue remodeling and resolution of the metabolic milieu that drives inflammation. Our central hypothesis is that skeletal muscle is a quantitatively important source of sRAGE appearance in the circulation and maintenance of healthy levels of total sRAGE promotes cardiometabolic health. The rationale is that once the mechanisms of ADAM10 activation and sRAGE generation are elucidated, progress towards the prevention and treatment of diabetic complications may be possible. Compelled by noteworthy preliminary data, we propose three specific aims to pursue our central hypothesis: (1) we will test the effects of acute and chronic exercise in generating sRAGE isoforms (2) we will determine the effects of acitretin therapy on RAGE mediated inflammation and (3) we will explore new protective effects of sRAGE in the microvasculature. The work is innovative because the study of RAGE ectodomain shedding in human skeletal muscle challenges the current understanding of AGE/RAGE biology and the known behavior of ADAM10 activity. At the completion of these studies, it is our expectation that we will have identified a novel mechanism of ADAM10 activation and an important tissue source of sRAGE production. Ultimately, such an insight has the potential to improve the prevention and therapeutic management of diabetes and its complications, thus reducing the financial and social burden that affects the ~347 million people worldwide with diabetes.

Public Health Relevance

The proposed research is relevant to public health because inflammation is the principle contributor to the development of complications associated with diabetes, which affects millions of individuals living with diabetes and their families. The research proposed herein is advantageous because we are targeting our body's natural ability to resolve inflammation through tissue and cellular turnover in response to exercise. Diabetes is killing our nation on multiple fronts through the physical inflictions the disease imposes on the body, the daily burden of care and the debilitating effects it poses on our healthcare system and economy. Thus, innovative approaches are needed to move the needle towards the direction of more efficacious and cost effective strategies for the treatment and prevention of diabetic complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK109948-05
Application #
9717242
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Jones, Teresa L Z
Project Start
2016-07-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Miranda, E R; Fuller, K N Z; Perkins, R K et al. (2018) Endogenous secretory RAGE increases with improvements in body composition and is associated with markers of adipocyte health. Nutr Metab Cardiovasc Dis 28:1155-1165
Mey, Jacob T; Haus, Jacob M (2018) Dicarbonyl Stress and Glyoxalase-1 in Skeletal Muscle: Implications for Insulin Resistance and Type 2 Diabetes. Front Cardiovasc Med 5:117
Mey, Jacob T; Blackburn, Brian K; Miranda, Edwin R et al. (2018) Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 314:R181-R190
Fuller, Kelly N Z; Miranda, Edwin R; Thyfault, John P et al. (2018) Metabolic Derangements Contribute to Reduced sRAGE Isoforms in Subjects with Alzheimer's Disease. Mediators Inflamm 2018:2061376
Miranda, Edwin R; Somal, Vikram S; Mey, Jacob T et al. (2017) Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes. Am J Physiol Endocrinol Metab 313:E631-E640