Adipose Tissue-Derived Extracellular Vesicles as Early Biomarkers of Type 2 Diabetes

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SUMMARY Obesity and type 2 diabetes (T2D) are interrelated pathological conditions frequently observed to lead to cardiovascular complications. Obesity-associated T2D is among the most-costly chronic diseases in the US, and a major cause of morbidity and mortality. There is a substantial latency period preceding T2D development, and many nascent T2D cases can be prevented if they are identified prior to tissue damage. Until now, there is still a lack of reliable clinical assay to identify high-risk individuals before the appearance of T2D clinical symptoms. Adipose tissue dysfunction is a central driver of T2D and adipose tissue is recently reported to produce extracellular vesicles (EVs), which can enter into circulation and influence whole-body glucose metabolism and contribute to the development of insulin resistance. Adipose tissue EVs released during disease progression represent excellent biomarker candidates for T2D risk prediction compared to traditional soluble adipokines, since adipose tissue EVs contain bio-active cargoes that act on target organs to promote insulin resistance and ultimately T2D. Adipose tissue EVs are also likely to be more stable in plasma than traditional soluble protein biomarkers that may be more likely to be degraded by serum protease activity. The assay that could specifically capture and quantify these adipose tissue EVs associated with T2D may, therefore, serve to early identify obese individuals at high risk for T2D before they exhibit any clinical symptoms. The overall objective of this study is to discover and validate novel EVs-based biomarkers for identifying obese individuals at high risk for the development of pre-T2D and T2D. In Aim 1, we propose to employ a quantitative proteomic labeling method to identify EV proteins specifically, or predominantly present in adipose tissue EVs isolated from obese patients with T2D, preT2D, or without T2D. These EV markers could serve as targets for probes to specifically detect T2D or preT2D-associated EV levels. To promote translation of EVs into clinical practice, we will utilize Aim 2 to adapt our innovative Nanoplasmon-enhanced scattering assay to quantify specific adipose tissue EVs associated with increased T2D risk using probes for EV markers and establish optimal conditions to detect T2D or preT2D-associated adipose tissue EVs, standardize the assay procedure, and evaluate the analytical performance of the assay. To more effectively translate adipose tissue EV markers into clinical application, we will validate the Nanoplasmonic assay for adipose tissue EV detection in plasma to permit early detection of increased T2D risk to guide therapeutic interventions intended to attenuate disease progression prior to tissue damage. To this end, Aim 3 proposes to employ the optimized Nanoplasmonic assay to evaluate adipose tissue EVs on T2D prediction in an obese population from the long-term Bogalusa Heart Study cohort, and establish a machine learning model to assess the EV markers both individually and in combination over and above a set of known factors for T2D prediction. I am confident to successfully complete the proposed Aims and develop into an independent investigator with the support of the COBRE program and guidance from the mentor team.