According to the World Health Organization, there are over 200 million people with diabetes with up to 1 million deaths attributed to diabetes annually, and these numbers are expected to double by 2030. Importantly, there has been a major increase in the incidence of diabetes in children and young adults with the increase in newly diagnosed T2 diabetes reaching over 40% of the new diabetes cases before the age of 20. Cardiovascular disease (CVD) begins to develop already in youth, and is marked by arterial stiffness. In youth with diabetes the arterial stiffness is markedly accelerated. The underlying mechanisms leading to this marked acceleration of arterial stiffening are not well understood and the current treatments have only limited efficacy. One of the key mechanisms leading to the arterial stiffness is endothelial dysfunction mediated by decrease in NO availability and increased inflammation. Recently, high-density lipoprotein (HDL) function, sterol efflux capacity was shown to be a strong predictor of incident and prevalent CVD independent of HDL-cholesterol (HDL-C) shifting the paradigm from HDL-C to HDL function as the metric for the HDL anti-atherogenic capacity. We have strong preliminary data showing that in adults HDL becomes dysfunctional a) in people with T2D, b) in people with endothelial dysfunction and c) in people with T1D and cardiovascular complications. Moreover, we have preliminary data showing that specific proteins in HDL can prospectively predict people at risk for cardiovascular events. We therefore hypothesize that changes in HDL composition and impaired HDL function in youth with diabetes may be novel risk factors contributing to accelerated arterial stiffness and increased cardiovascular risk found in this population. We propose to use our state-of-the-art assays to investigate whether HDL composition and function associates with increased arterial stiffness in youth with diabetes: first, we will establish the changes in HDL composition and function in youth with T1D or T2D compared to healthy controls. We will then investigate the role of HDL in arterial stiffening in two complementary studies nested in SEARCH study. First study will address whether our novel metrics of HDL function associate with increased arterial stiffness in youth with T2D. Second study will address the same question in youth with T1D. In parallel in the longitudinal Barbara Davis Center study of youth with T1D we will test whether changes in HDL metrics associate with changes in arterial stiffness and whether the baseline HDL metrics can predict progression of arterial stiffness. Collectively, our studies have great potential to discover novel roles for HDL function in early stages of atherosclerosis progression, and, will advance our understanding of the physiology of the arterial stiffness and increased cardiovascular risk in youth with diabetes. Identification of novel molecular risk factors and biological pathways related to arterial stiffness in the youth has the potential to identify novel biomarkers and therapeutic targets, and contribute to the efforts to reduce the CVD mortality associated with diabetes, a critical area of research in the face of the rapidly increasing incidence of juvenile diabetes.

Public Health Relevance

Arterial stiffness is one of the first marks of cardiovascular disease and it is already increased in youth with diabetes even before the age of 20. This proposal focuses on the role of high-density lipoprotein composition and function as novel risk factors for the accelerated arterial stiffness, a marker of cardiovascular disease in youth. The results may lead to better understanding the mechanisms of arterial stiffness worsening in youth and identification of novel targets for therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Reis, Jared P
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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